2. Antibiotic Strategy in Nosocomial
Pneumonia
Gamal Rabie Agmy, MD,FCCP
Professor of Chest Diseases, Assiut university
ERS National Delegate of Egypt

4. ANTIMICROBIAL DRUGS

5. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
 Mechanism of action
include:
 Inhibition of cell wall
synthesis
 Inhibition of protein
synthesis
 Inhibition of nucleic acid
synthesis
 Inhibition of metabolic
pathways
 Interference with cell
membrane integrity

6. MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
 Inhibition of Cell wall synthesis
 Bacteria cell wall unique in
construction
 Contains peptidoglycan
 Antimicrobials that interfere with
the synthesis of cell wall do not
interfere with eukaryotic cell
 Due to the lack of cell wall in
animal cells and differences in cell
wall in plant cells
 These drugs have very high
therapeutic index
 Low toxicity with high effectiveness
 Antimicrobials of this class include
 β lactam drugs
 Vancomycin
 Bacitracin

7.  Inhibition of protein synthesis
 Structure of prokaryotic ribosome acts as target for
many antimicrobials of this class
 Differences in prokaryotic and eukaryotic ribosomes
responsible for selective toxicity
 Drugs of this class include
 Aminoglycosides
 Tetracyclins
 Macrolids
 Chloramphenicol
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS

8.  Inhibition of nucleic acid synthesis
 These include
 Fluoroquinolones
 Rifamycins
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS

9. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
 Inhibition of metabolic
pathways
 Relatively few
 Most useful are folate
inhibitors
 Mode of actions to
inhibit the production
of folic acid
 Antimicrobials in this
class include
 Sulfonamides
 Trimethoprim

10. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
 Interference with cell
membrane integrity
 Few damage cell
membrane
 Polymixn B most common
 Common ingredient in
first-aid skin ointments
 Binds membrane of Gram
- cells
 Alters permeability
 Leads to leakage of cell
and cell death
 Also bind eukaryotic cells
but to lesser extent
 Limits use to topical
application

11. EFFECTS OF
COMBINATIONS OF DRUGS
 Sometimes the chemotherapeutic effects of
two drugs given simultaneously is greater than
the effect of either given alone.
 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
 Other combinations of drugs can be
antagonistic.
 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
 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.

14. Pharmacology
Pharmacokinetics
Pharmacodynamics

15. Pharmacokinetics
• Time course of drug absorption,
distribution, metabolism, excretion
How the drug
comes and goes.

16. “LADME” is key
Pharmacokinetic Processes
Liberation
Absorption
Distribution
Metabolism
Excretion

17. Pharmacodynamics
• The biochemical and physiologic
mechanisms of drug action
What the drug
does when it gets there.

18. Concepts
Pharmacokinetics
– describe how drugs behave in the human host
Pharmacodynamics
– the relationship between drug concentration
and antimicrobial effect. “Time course of
antimicrobial activity”

19. Minimum Inhibitory Concentration (MIC)
– The lowest concentration of an antibiotic that inhibits
bacterial growth after 16-20 hrs incubation.
Minimum Bacteriocidal Concentrations.
– The lowest concentration of an antibiotic required to
kill 99.9% bacterial growth after 16-20 hrs exposure.
C-p
– Peak antibiotic concentration
Area under the curve (AUC)
– 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 “sufficient” number
of active sites.
Antibiotic must reside on the active site for
“sufficient” time. Antibiotics are not contact
poisons.

21. Static versus Cidal
Control
Cidal
StaticCFU
Time

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
– 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
– Higher concentration greater killing
Aminoglycosides, Flouroquinolones, Ketolides,
metronidazole, Ampho B.
Time-dependent killing
– Minimal concentration-dependent killing (4x
MIC)
– More exposure more killing
Beta lactams, glycopeptides, clindamycin,
macrolides, tetracyclines, bactrim

27. Persistent Effects
Persistent suppression of bacterial growth
following antimicrobial exposure.
– Moderate to prolonged against all GM
positives (In vitro)
– Moderate to prolonged against GM negatives
for protein and nucleic acid synthesis
inhibitors.
– Minimal or non against GM negatives for beta
lactams (except carabapenems against P.
aeruginosa)

28. Post-antibiotic sub-MIC effect.
– Prolonged drug level at sub-MIC augment the
post-antibiotic effect.
Post-antibiotic leukocyte killing enhancement.
– Augmentation of intracellular killing by
leukocytes.
– The longest PAE with antibiotics exhibiting this
characteristic.
Persistent Effects

29. Patterns of Antimicrobial Activity
Concentration dependent with moderate to
prolonged persistent effects
– Goal of dosing
Maximize concentrations
– PK parameter determining efficacy
Peak level and AUC
– Examples
Aminoglycosides, Flouroquinolones, Ketolides,
metronidazole, Ampho B.

30. Time-dependent killing and minimal to
moderate persistent effects
– Goal of dosing
Maximize duration of exposure
– PK parameter determining efficacy
Time above the MIC
– Examples
Beta lactam, macrolides, clindamycin, flucytosine,
linezolid.
Patterns of Antimicrobial Activity

31. Patterns of Antimicrobial Activity
Time-dependent killing and prolonged
persistent effects
– Goal of dosing
Optimize amount of drug
– PK parameter determining efficacy
AUC
– Examples
Azithromycin, vancomycin, tetracyclines,
fluconazole.

32. PK/PD patterns
Concentration
MIC
Time
AUC AUC
C-p C-p

33. Antibacterial spectrum — 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 activity— -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 activity— 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 binations— 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 — Com binations of
two antibiotics that have enhanced
bactericidal activity when tested together
com pared with the activity of each
antibiotic.
Antibiotic antagonism — 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 ase— 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.

34. Resistance
Physiological Mechanisms
1. Lack of entry – tet, fosfomycin
2. Greater exit
 efflux pumps
 tet (R factors)
3. Enzymatic inactivation
 bla (penase) – hydrolysis
 CAT – chloramphenicol acetyl transferase
 Aminogylcosides & transferases
REVIEW

35. Resistance
Physiological Mechanisms
4. Altered target
 RIF – altered RNA polymerase (mutants)
 NAL – altered DNA gyrase
 STR – altered ribosomal proteins
 ERY – methylation of 23S rRNA
5. Synthesis of resistant pathway
 TMPr plasmid has gene for DHF reductase;
insensitive to TMP
(cont’d)
REVIEW

36. Resistance to β-Lactams – Gram pos.
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
(cont’d)
REVIEW

37. Resistance to β-Lactams – Gram neg.
Mechanism of Action
CELL WALL SYNTHESIS INHIBITORS
(cont’d)
REVIEW

38. The Ideal Drug*
1. Selective toxicity: against target pathogen but
not against host
 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 “side effects”
 Therapeutic index: effective to toxic dose ratio
6. Little resistance development

39. 39
Pneumonias – Classification
• Community AcquiredCAP
• Health Care AssociatedHCAP
• Hospital AcquiredHAP
• ICU AcquiredICUAP
• 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:
•Fever (core temperature >38°C),
• Leukocytosis (>10000mm-3) or leukopenia (<4000mm-3),
•Purulent tracheal secretions,
•Increased oxygen requirements, reflecting new or
worsening hypoxaemia.
Diagnosis

43. Sensitivity Specificity
Clinical estimate 50% 58%
CPIS score > 6* 60% 59%
BAL Gram stain 85% 74%
Telescoping catheter 60% 90%
CPIS + BAL Gram
stain
85% 49%
CPIS + telescoping
catheter
78% 36%

45. *Hypotension.
*Sepsis syndrome.
*End organ dysfunction.
*Rapid progression of infiltrates.
*Intubation
Severe HAP

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 ≥5 days (late-onset
infection)
Prior antibiotic therapy
Particularly in the prior 2 weeks
Recent hospitalisation in the preceding 90 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
care–associated 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 anti– 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 2 g every 8 h + aminoglycoside (Amikacin
20 mg·kg−1·day−1) or quinolone (Levofloxacin 750 mg i.v.
HAP with risk factors for
Gram-negative bacilli Chronic underlying disease Antipseudomonal β-lactam± aminoglycoside or quinolone
Cefepime 1–2 g every 8–12 h i.v.
Carbapenems¶: imipenem 500 mg every 6 h or 1 g every
8 h i.v.; or meropenem 1 g every 8 h i.v.; or
ertapenem+ 1 g·day−1i.v.
P. aeruginosaand multi-
resistant Gram-negative
bacilli
Wide-spectrum antibiotics, severe
underlying disease, ICU stay
Antipseudomonal β-lactam±aminoglycoside or quinolone
Cefepime 1–2 g every 8–12 h i.v.
β-lactamic/β-lactamase inhibitor: piperacillin-tazobactam
4.5 g every 6 hi.v.
Carbapenems¶: imipenem 500 mg every 6 h or 1 g every
8 h i.v.; or meropenem 1 g every 8 h i.v.
Legionella#
Hospital potable water colonisation and/or
previous nosocomial Legionellosis
Levofloxacin 500 mg every 12–24 h i.v.or 750§ mg every
24 h i.v. or azitromycin 500 mg·day−1 i.v.
Anaerobes
Gingivitis or periodontal disease,
depressed consciousness, swallowing
disorders and orotracheal manipulation
Carbapenems¶: imipenem 500 mg every 6 h or 1 g every
8 h i.v.; or meropenem 1 g every 8 h i.v.; or
ertapenem+ 1 g·day−1i.v.
β-lactam/β-lactamase inhibitor amoxicillin/clavulanate 2 g
every 8 hi.v.¶; piperacillin-tazobactam 4.5 g every 6 h i.v.
MRSA
Risk factors for MRSA or high prevalence
of MRSA
Vancomycin 15 mg·kg−1 every 12 h i.v.Linezolid 600 mg
every 12 h i.v.
Aspergillus
Corticotherapy, neutropenia or
transplantation
Amphotericyn B desoxicolate 1 mg·kg−1·day−1 i.v. or
amphotericyn liposomal 3–5 mg·kg−1·day−1 i.v.Voriconazol
6 mg·kg−1 every 12 h i.v.(day 1) and 4 mg·kg−1 every
12 h i.v.(following days)
Early-onset HAP <5 days Without risk factors and non-severe
β-lactam/β-lactamase inhibitor: amoxicillin/clavulanate 1–2 g
every 8 hi.v.
Third generation non-pseudomonal cephalosporin:
ceftriaxone 2 g·day−1i.v./i.m. or cefotaxime 2 g every 6–8 hi.v.
Fluoroquinolones: levofloxacin 500 mg every 12–24 h i.v. or
750§ mg·day−1 i.v.
Late-onset HAP ≥ 5 days Without risk factors and non-severe
Antipseudomonal cephalosporin (including pneumococcus):
cefepime 2 g every 8 h i.v.
Fluoroquinolones: levofloxacin 500 mg every 12–24 h i.v. or
750§ mg·day−1 i.v.