4. Why does Pseudomonas
aeruginosa colonization
happen?
Significant and/or prolonged colonization by
P. aeruginosa occurs following loss of
resistance to colonization
5. How is the resistance to
colonization lost?
1. Changes in the composition of normal
microbiota secondary to antibiotic treatment.
2. Pre-existence of severe disease.
7. How common is
Pseudomonas aeruginosa
infection?
• Second most common nosocomial infection.
• Third most common community acquired
infection.
8. How deadly is
Pseudomonas aeruginosa
infection?
• 20-39% in case of bacteremia.
• 44% in case of VAP.
9. What is the clinical
classification of
Pseudomonas aeruginosa
infection?
• Acute superficial, non-invasive.
• Acute invasive infection.
• Chronic infection.
10. Acute superficial, non-
invasive infection.
• Examples include external otitis, paronychia and
folliculitis.
• Often self limited or respond to oral ciprofloxacin.
• Less likely to harbor or develop resistance.
11. Acute invasive infection
• Examples include bacteremia, pneumonia, peritonitis,
uti and venous catheter infection.
• Severity of infection and risk of resistance make
empirical treatment inadequate or generate higher
degree of resistance.
12. Chronic infection
• Usually less virulent and rarely produce
bacteremia.
• Biofilms make eradication difficult.
14. Mechanisms of intrinsic resistance
1. β-lactamase. (Against penicillins and
cephalosporins)
2. Efflux pumps. (Against β-lactams except
imipinem, flouroquinolones and
aminoglycosides)
3. Lipopolysaccharide modification. (Against
polymyxins)
15. Why does adaptive
resistance happen?
• Due to selection of mutations responsible for resistance
development (The rate of spontaneous mutation
ranges from 1 mutant per million bacteria to 1 mutant
per 100 millions).
• Transferable genetic elements as plasmids.
16. How?
• High Bacterial load.
• Hypermutator strains. (1000 times rate of
spontaneous mutation)
• MPC.
18. MIC And MPC
• Mimimum inhibitory
concentration (MIC) is
the lowest
concentration of an
antimicrobial that will
inhibit the visible
growth of a
microorganism after
overnight incubation
(Andrews JM, 2001).
• Mutant prevention
concentration (MPC) is
the drug concentration
that allows no mutant
to be recovered from a
susceptible population
(Dong Y et al, 1998).
19. Principles for the treatment of
infection by Pseudomonas
aeruginosa
1. MIC.
2. Bacterial load.
3. Mutation ability and development of resistance.
4. Importance of empirical antibiotic treatment.
5. Value of antibiotic associations.
6. Clinical efficacy of monotherapy.
7. Measurements to increase antibiotic
concentration in the infectious foci.
21. MIC
High doses of β-lactams are recommended
•The breakpoint used to categorize Pseudomonas
aeruginosa as resistant to one β-lactam or
aminoglycoside is from 2-times to 8-times higher
than the one used to consider resistant an
enterobacteria.
22. MIC (continued)
Time of exposure
• Definitions: it is the percentage of time that the
free fraction exceeds MIC.
• Elimination half life of β-lactams is 1-2 hours, after
the 4th - 6th hour drop below 4-8mg/l.
• In septic patients increased volume of distribution
and increased renal clearance decrease the time of
exposure.
23. MIC (continued)
A loading dose of β-lactams followed by giving the
total daily dose by continous infusion was more
efficacious than intermittent dosing in respect to:
•Clinical cure rate.
•Microbiological eradication.
•Days with fever.
•Days of hospital stay.
•Mortality.
24. MIC (continued)
Aminoglycosides
The greatest efficacy for treatment is obtained when
the maximum concentration exceeds the MIC 10
times which is not achieved with standard doses.
26. Bacterial load
• Infections with high bacterial load include
pneumonia, ventilator associated purulent
tracheobronchitis and peritonitis.
• Bacterial load is 100-1000 times higher than the
standard in vitro susceptibility tests.
• High bacterial load increase selection of resistant
mutants.
• At higher bacterial load bacteriolytic activity of
granulocytes is surpassed and bacterial growth
occur.
27. Bacterial load (continued)
The intrinsic activity of most antibiotics is
decreased when the bacterial load is high
•Due to the reduced growth rate with reduced
affinity to β-lactams and the increase of β-lactamase
concentration due to bacterial lysis.
•For β-lactams time over MIC is the most important
factor at low bacterial load, however,β-lactam
activity shows certain dependence on the antibiotic
concentration at high bacterial load.
30. Mutation ability
Rate of spontaneous mutation is increased with
•Agents damaging DNA as flouroquinolones.
•Biofilm embedded bacterial growth.
•High bacterial load more 10,000,000-100,000,000
CFU.
31. Mutation ability (continued)
How to counter the development of resistance
•Reduction of bacterial load by drainage, debridment
or removal of catheter.
•The use of doses and/or routes of administration
able to generate an antibiotic concentration higher
than MIC for potential resistant mutants.
•Associations of antibiotics not sharing the same
resistance mechanisms.
32. Mutation ability (continued)
After 48-72 hours
If the oraganism is susceptible and the dose/route of
administration are appropriate, administration of an
aminoglycoside is not justified as the bacterial load
should be lower than needes to generate resistant
mutants and thus continuing treatment with a β-
lactam as a monotherapy is recommended.
34. Importance of an appropriate
empirical treatment.
• If the initial empirical antibiotic treatment is not
appropriate higher mortality rates were observed.
• Non appropriate antibiotics are those for which the
microorganism shows resistance in in vitro
susceptibility.
• A β-lactam associated with amikacin, ciprofloxacin or
colistin (chosen based on local resistance rates)
increases the probability of the appropriateness of
the initial empirical schedule.
36. Value of antibiotic associations
The association of a β-lactam and an
aminoglycoside shows in vitro synergistic activity
•Most studies didn't find significant difference in
mortality between monotherapy and association
group.
•The studies that found favorable effect of
association were non conclusive.
37. Value of antibiotic associations
(continued)
Causes of the apparent lack of in vivo synergy
•Concentration.
•Adaptive resistance.
•Limited diffusion.
38. Value of antibiotic associations
(continued)
When to recommend an antibiotic association
•During the first 72 hours if the infection presents
criteria of severe sepsis or septic shock.
•In the neutropenic patient.
•In central nervous system or endovascular infection.
•In the treatment of infections caused by β-lactam
resistant pathogen.
40. Clinical efficacy of monotherapy
• β-lactams show higher efficacy and lower toxicity
than aminoglycosides or colistin.
• Flouroquinolones show similar efficacy to β-lactam
but may have advantages over a β-lactam, based
on the possibility of oral administration, better
penetration in the infectious foci as in cystic fibrosis
bronchial infections and the probable greater
activity in biofilms.
42. Measures to increase antibiotic
concentration in the infectious foci
• As inhalatory and intrathecal route.
• Antibiotic concentration is 100 times higher than
obtained by the same dose by iv route.
• Useful even against resistant organisms.
• Addition of an inhaled antibiotic to intravenous
treatment improves clinical success and
microbiological eradication.
45. New agents
• Ceftolazone-tazobactam.
• Ceftazidime-avibactam.
• Active against 80-95% of isolates.
• Have low risk of mutant selection due to low MPC
(2mg/l).
46. β-lactams
• High doses and extended or continuous infusion
after an initial loading dose.
• High risk of mutant selection except meropenem
showing moderate risk.
• Side effects include neurotoxicity especially with
cefepime and delay of restoration in renal function
with piperacillin-tazobactam.
47. Aminglycosides
• Tobramycin is 4 times more active than amikacin
but against only 80% of isolates compared to 95%.
• The recommended dose in the first 48-72 h of
treatment, in patients with normal renal function
and severe P. aeruginosa infection, is up to 8
mg/kg for gentamicin or tobramycin and of 20-30
mg/kg for amikacin.
48. Flouroquinolones
• Ciprofloxacin is intrinsically more active than
levofloxacin.
• The bactericidal effect of fluoroquinolones is slower
than that of aminoglycosides and lysis of resistant
mutants requires longer exposures.
• Levofloxacin diffusion to CSF, lung parenchyma and
bronchial secretion is superior to β-lactams,
aminoglycosides and colistin.
• High doses might produce neurotoxicity.
49. Flouroquinolones (continued)
In vitro studies show
•Association of levofloxacin with imipinem prevented
emergence of resistant strains.
•Association of levofloxacin with meropenem had
more rapid bactericidal effect and resulted in
resistance suppression even when the strain was
resistant to levofloxacin.
50. Colistin
• Active against 98% of Pseudomonas aeruginosa
strains.
• Colistin should not be used as monotherapy,
especially if the MIC is > 1 mg/L, the bacterial load
is high or in the case of low accessible foci.
• Synergism is observed with association with β-
lactams, flouroquinolones or rifampicin.
• A delay of 48-72 is needed to reach the stationary
state with iv dosing.
51. Colistin (continued)
• Addition of a loading dose showed no difference in
mortality but showed more frequent renal toxicity
and appearance of seizures.
• Diffusion to alveolar spaces, bronchial secretion
and CSF is limited.
52. ANTIBIOTICS OF CHOICE
FOR THE TREATMENT OF
INFECTIONS CAUSED BY P.
aeruginosa
• Empirical treatment.
• Directed treatment.
53. Empirical treatment
• High bacterial load not surgically correctable (extensive
pneumonia or pneumonia with necrosis/cavitation).
• Neutropenia < 500 cells/mm3 and treatment with
corticoid doses >20 mg/kg during >3 weeks.
• Treatment within the last 30-90 days with a β-lactam
active against P. aeruginosa.
• Admission for > 3-5 days in a hospital unit with a
prevalence of MDR P. aeruginosa >10-20% or previous
history of colonization/infection by MDR P. aeruginosa.
54. Empirical treatment (continued)
If the patient fullfils any of the previous criteria
give:
•A β-lactam different from the one received within
the previous 90 days.
•Meropenem>ceftazidime >piperacillin-tazobactam.
•Add a second antibiotic taking into account the
epidemiology of the unit.
•Amikacin or colistin.
55. Empirical treatment (continued)
If the patient doesn't fullfil the previous criteria
give:
•β-lactam as monotherapy or associated with
amikacin or ciprofloxacin when bacterial load is high.
•From the 3rd day on treatment can be continued
as monotherapy with a β-lactam chosen in
accordance with the antibiogram.
• Ciprofloxacin as treatment of choice for bronchial
infection in cystic fibrosis.
56. Directed treatment
Strain resistant to one of the β-lactams active
against P. aeruginosa.
•In case of resistance to ceftazidime and/or
piperacillin-tazobactam.
•Meropenem can be appropriate in cases with low
bacterial load.
• If resistant to meropenem give ceftazidime or
piperacillin-tazobactam.
57. Directed treatment (continued)
Strain susceptible to all β-lactams
•There is high risk of resistance emergence with the
use of meropenem, ceftazidime and piperacillin-
tazobactam.
59. Directed treatment (continued)
Inhaled antibiotic (Tobramycin or Colistin)
•Reserved for severe pneumonia or pneumonia
caused by Pseudomonas aeruginosa MDR.
•Should be considered in intubated patients and
patients with chronic bronchial pathology in which
the high bacterial load and limited diffusion of
antibiotics can lead to treatment failure and/or
resistance emergence.
60. CNS infection
• Problems include limited diffusion of antibiotics
and the risk of encephalopathy (seizures)
associated with elevated doses of β-lactams.
• Meropenem or ceftazidime +/- ciprofloxacin.
• Intrathecal tobramycin, amikacin or colistin if
susceptible.
61. Take home message
• High dose β-lactams should be given by extended
or continuous infusion with an initial loading dose.
• Aminoglycosides' activity is concentration
dependent, appropriate concentration is reached
by local route rather than iv route.
• Ciprofloxacin is more effective in patients with
cystic fibrosis.
• Selection of a first mutation facilitates the selection
of others so hit early and hit hard.
62. References:
• Andrews JM. Determination of minimum inhibitory
concentrations. J Antimicrob Chemother. 2001
Jul;48 Suppl 1:5-16.
• Dong Y et al. Mutant Prevention Concentration as a
Measure of Antibiotic Potency: Studies with Clinical
Isolates ofMycobacterium tuberculosis.
Antimicrobial Agents and Chemotherapy. 2000
sep;44(9):2581-2584;