Antibiotics, Antibiotics

Combination and
Reasons Resistance
for appropriate use
Avoid adverse effects on the patient
Avoid emergence of antibiotic
resistance - ecological or societal aspect
of antibiotics
Avoid unnecessary increases in the cost
of health care
Choice
Aetiological agent
of an
antibiotic
Patient factors
Antibiotic factors

The
aetiological
agent
 Importance of local
antibiotic
The resistance
aetiological agent data
Patient factors
Age
Physiological functions
Genetic factors
Pregnancy
Site and severity of infection
Allergy
 Antibiotic
factors
Pharmacokinetic/pharmacodynamic (PK/PD) profile
absorption
excretion
tissue levels
peak levels, AUC, Time above MIC
Toxicity and other adverse effects
Drug-drug interactions
Cost
 PK/PD
Parameters
Increasing knowledge on the association
between PK/PD parameters on clinical
efficacy and preventing emergence of
resistance
Enabled doctors to optimise dosage regimens
Led to redefinition of interpretative
breakpoints in sensitivity testing
 Antimicrobial
activityPeak (Peak/MIC)
Drug Concentration

Area Under the Curve (AUC/MIC)

MIC

Time above MIC

Time
 Important PK/PD
Parameters
AUC/MIC is the
ratio of the Area under the curve
over MIC

concentration
AUC to MIC
Antibiotic
PEAK

Peak/MIC is the
ratio of the MIC
peak
concentration
Time
to MIC
 Antimicrobial
2 main patterns of bacterial killing
Efficacy
Concentration dependent
Aminoglycosides, quinolones,
macrolides, azalides, clindamycin,
tetracyclines, glycopeptides,
oxazolidinones
Correlated with AUC/MIC , Peak/MIC
Time dependent with no persistent
effect
Betalactams
Correlated with Time above MIC
(T>MIC) Craig, 4 ISAAR, Seoul 2003
th
 Goal of therapy
based on PK/PD
Pattern of Activity Antimicrobials
Concentration dependent AMGs, Quinolones,
killing Daptomycin, ketolides,
Macrolides, azithro-mycin,
clindamycin,
streptogramines,tetracyclin
es, glycopeptides,
oxazolidinones
Time dependent killing Betalactams
with no persistent effects
Goal of therapy and
relevant PK/PD
Parameter
Maximise
concentrations;
AUC/MIC, peak/MIC
Use high doses; daily
dosing for some
agents
Maximise duration of
exposure; T>MIC
Use more frequent
dosing; longer infusion
times including
continuous infusion
 Duration of
treatment
In most instances the optimum duration is
unknown
Duration varies from a single dose to many
months depending on the infection
Shorter durations, higher doses
For certain infections a minimum duration is
recommended
 minimum
Infection
durations of
Minimum duration
Tuberculosis treatment 4 - 6 months
Empyema/lung abscess 4 - 6 weeks
Endocarditis 4 weeks
Osteomyelitis 4 weeks
Atypical pneumonia 2 - 3 weeks
Pneumococcal meningitis 7 days
Pneumococcal 5 days
pneumonia
 Monitoring
efficacy
Early review of response
Routine early review
Increasing or decreasing the level of treatment
depending on response
change route
change dose
change spectrum of antibacterial activity
stopping antibiotic
 Clinical Use of
Antimicrobial
Prevention of the emergence of resistant
Combinations
organisms
Polymicrobial infection
Initial therapy
Decreased toxicity
Synergism
 Emergence of
Resistant
Decreased resistant mycobacterium
Organisms
tuberculosis with combination
treatment of
Reduction of -lactamase induction
with combination -lactam agents and
aminoglycosides
 Polymicrobial
Infection
Intraabdominal infection: ciprofloxacin and
metronidazole
Pelvic infection
Mixed aerobic and anaerobic organism
Availability of broad spectrum antibiotics such as
carbapenems and -lactam- -lactamase inhibitors
restrict the use of combination antibiotics
 Initial
Therapy
Neutropenic patients: Ceftazidime and
vancomycin
In patients where the nature of infection is
not clear yet: high dose ceftriaxone along
with vancomycin in suspected pneumococcal
meningitis in areas of high rate of penicillin
resistance
 Decreased
Toxicity
Decrease the toxic drug required for treatment
and thus reduce the dose related toxicity
No data from clinical trials that establish
without doubt that combination therapy with
different agents permits a reduction of the drug
dose sufficient to reduce dose-related toxicity
Synergism
Enhanced Uptake ofendocarditis: ampicillin and
Treatment of enterococcal
Aminoglycoside
gentamicin when Combined
with -lactam
Viridans agents
streptococcal endocarditis: penicillin and
gentamicin
Staphylococcal bacteremia: vancomycin and
gentamicin
Treatment of pseudomonas infections: -lactam agent
and aminoglycosides
Synergism
Inhibition of Sequential
Steps
Sulfonamide with trimethoprim
Treatment and prevention of chronic
urinary tract infection, typhoid fever
and shigellosis caused by organisms
resistant to ampicillin
Inappropriate Use of
Antimicrobial
Combination
Antagonism
Increased cost
Adverse effects
Superinfection
Resistan
To be effective antimicrobial must reach
the target and bind to it.

ce
Resistance:
Failure to reach the target
The drug is inactivated
The target is altered
Resistanc
Bacteria produce enzymes at or within the cell
surface inactivate drug

e (cont.)
Bacteria possess impermeable cell membrane prevent
influx of drug.
Transport mechanism for certain drug is energy
dependent- not effective in anaerobic environment.
Drug as organic acids penetration is pH dependent.
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Antimicrobial Resistance:
Key Prevention Strategies
Susceptible Pathogen
Antimicrobial-Resistant
Pathogen Pathogen
Prevent Prevent
Transmission Infection

Infection
Antimicrobial
Resistance
Effective
Optimize Diagnosis
& Treatment
Use

Antimicrobial Use
12 Steps to
Prevent
1. Vaccinate

Antimicrobial
2. Get the catheters out
3. Target the pathogen
4. Access the experts
Resistance
5.
6.
Practice antimicrobial control
Use local data
7. Treat infection, not contamination
8. Treat infection, not colonization
9. Know when to say no to vanco
10. Stop treatment when cured
11. Isolate the pathogen Prevent Transmission
12. Break the chain Use Antimicrobials Wisely
Diagnose & Treat Effectively
Prevent Infections