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Antibiotics
One of the most commonly used
group of drugs
May account for up to 50% of a
hospitals drug expenditure
Studies worldwide has shown a high
incidence of inappropriate use
What is misuse of antibiotics?
Misuse of antibiotics can include any of the following18:
When antibiotics are prescribed unnecessarily;
When antibiotic administration is delayed in critically ill
patients;
When broad-spectrum antibiotics are used too
generously, or when narrow-spectrum antibiotics are
used incorrectly;
When the dose of antibiotics is lower or higher than
appropriate for the specific patient;
When the duration of antibiotic treatment is too short or
too long;
When antibiotic treatment is not streamlined according to
microbiological culture data results.
18. Gyssens IC, van den Broek PJ, Kullberg BJ, Hekster Y, van der Meer JW. Optimizing antimicrobial therapy. A method
for antimicrobial drug use evaluation. J Antimicrob Chemother. 1992 Nov;30(5):724-7.
Prescribing an antibiotic
Is an antibiotic necessary ?
What is the most appropriate
antibiotic?
What dose, frequency, route and
duration ?
Is the treatment effective ?
Infeksi Penyakit infeksi
Mikroorganisme
infeksi
Tubuh manusia
Tempat infeksi
Tipe infeksi
Sumber infeksi
Keadaan klinis pasien
Faktor obat / antibiotik
Sensitivitas kuman terhadap antibiotik
Bacteria by Site of Infection
Mouth Skin/Soft Tissue Bone and Joint
Peptococcus S. aureus S. aureus
Peptostreptococcus S. pyogenes S. epidermidis
Actinomyces S. epidermidis Streptococci
Pasteurella N. gonorrhoeae
Gram-negative rods
Aetiological agent
Patient (host) factors
Antibiotic (drug) factors
Selection of Antimicrobial Therapy:
Pathogen Factors
Susceptibility patterns
Vary from institution to institution and even among nursing units
Change quickly if resistant clone becomes established and spreads
Antibiograms are available from the laboratory at most hospitals and
updated regularly, and are essential to choose appropriate empirical
therapy
Using MIC (minimum inhibitory concentration) data
Requires knowledge of achievable drug concentrations at the site of
infection
Comparisons within a class of antibiotics can be helpful; example =
Tobramycin with an MIC of <1mcg/ml for P aeruginosa is preferred
over gentamicin with MIC of 4 for that organism
Pemberian antibiotik yang rasional
SOP
POLA
INFEKSI KULTUR
KEPEKAAN
EDUCATED
ANTIBIOTIKA GUESS
THERAPY
DOSIS
& CARA
EVALUASI
menguji kepekaan bakteri patogen secara in vitro
terhadap antimikroba
UJI
KEPEKAAN
Antibiotic
resistance Infection
Optimize Effective
use diagnosis
and treatment
Antibiotic
use
Selection of Antimicrobial Therapy:
Host Factors
Allergies, age, pregnancy, hepatic and renal function,
concomitant drug therapy, immunocompentence,
and co-morbidities
Site of infection
Must cover common pathogens for specific infectious
diagnosis until culture results return
Must consider temporal relationships
Organisms differ with early vs late onset hospital-acquired
pneumonia
Organisms may reflect selective pressure if antibiotics
previously administered (Antimicrobial history taking is
extremely important!)
Selection of Antimicrobial Therapy:
Drug Factors
Variable antibiotic tissue penetration
Protected sites: pulmonary secretions, the central nervous system,
eye, prostate, abscess, bone
Drug clearance: many are renally cleared
Exceptions: the macrolides, amphotericin, caspofungin, voriconazole,
clindamycin, tetracyclines, moxifloxacin, linezolid, ceftriaxone, and the
antistaphylococcal penicillins
Bioavailability
Good absorption for most quinolones, linezolid, cotrimoxazole,
metronidazole, fluconazole, voriconazole, clindamycin, cephalexin,
doxycycline, minocycline
Toxicity profile
Cost truths:
generic cheaper than brand name and oral/enteral cheaper than
parenteral, BUT: antimicrobial costs represent a small fraction of
infection treatment
Bacterial growth curve
Minimum inhibitory
concentration (MIC)
The lowest concentration of drug that
prevents visible bacterial growth after 24
hours of incubation in a specified growth
medium
To determine it we use serial dilutions of
AB
SEE NEXT SLIDE
Organism and antimicrobial specific
Relationship between PK and PD
Concentration
Pharmacologic
vs time in
or toxicologic
tissue and
effect
other body fluids
Concentration
Dosage vs time in
regimen plasma Concentration
vs time in Antibiotic
Absorption site of effect vs time
Protein binding
Distribution infection
Biotransformation
Excretion
pharmacokinetics pharmacodynamics
Post-antibiotic
effect (PAE)
Post antibiotic effect (PAE)
Persistant suppression of microbial growth
that occurs after depletion of antibiotic
concentration
Length of time it takes to achieve log
phase of growth
AB exhibiting long PAE require only one
dose per day
Aminoglycosides and fluroquinolones
Important PK/PD Parameters
concentration dependent
over MIC
Antibiotic
Cmax to MIC
Cmax/MIC is the
MIC ratio of the peak
concentration
to MIC
Time
Important PK/PD Parameters
time dependent
Proportion of the
6 dosing interval
Drug B
(ug/ml)
12
Concentration (mg/L)
Once-daily regimen
Conventional
8
(three-times daily regimen)
MIC
0
0 8 16 24
Time (hours)
Nicolau et al. Antimicrob Agents Chemother 39:6505,1995
Time-dependent antibiotics
Sustained-release technology and materials used in Extended release (ER) vs
Drug
the products immediate-release (IR)
The tablet contains an immediate-release granulation
(45% of the dose) and two delayed-release pellets, Pulse
Longer T>MIC than
2 (30% of the dose) and Pulse 3 (25% of the dose). The
Amoxicillin amoxicillin suspension
delayed-release pellets release amoxicillin in a different
(13.3 h vs 11.7 h)
region of the intestinal tract subsequent to reaching the
pH trigger for each of the respective film coats.
The tablet consists of a bilayer tablet, with one layer
Amoxicillin/ containing immediate-release amoxicillin trihydrate (56% Higher rate of treatment
clavulanate of the dose) and clavulanic acid, and the other layer success
potassium containing sustained-release sodium amoxicillin (44% of Lower treatment cost
the dose). The main inactive ingredient is hypromellose.
The tablets are formulated using a patented polymer- Improved patient
based matrix that slows the release and extends compliance
Clarithromycin absorption from the gastrointestinal tract. The polymer is Enhanced gastrointestinal
a water-soluble hydrophilic polymer. More preferably, the tolerability and improved
polymer is hydroxypropylmethyl cellulose. taste profile
(1) Shorter regimen
The delivery system has a slower rate of dissolution
(2) Lower and later steady-
Cefaclor owing to the hydrophilic polymer that forms a gel layer on
state peak plasma
contact with gastrointestinal fluids independent of pH.
concentrations
(1) Reduced dose-related
adverse events and
Minocycline The tablet contains hypromellose type 2910 and
inflammatory lesions
hydrochloride carnauba wax as the matrix materials.
(2) Improved therapeutic
effect
Meropenem 500 mg Administered
as a 3 h Infusion Extends the Time Over the MIC vs a 0.5 h
infusion
100.0
Rapid Infusion (30 min)
Concentration (mcg/mL)
1.0
MIC
Additional T>MIC gained
0.1
0 2 4 6 8
Time (h)
Yes No
Almost all cephalosporins and Doxycycline
most other beta-lactams Erythromycin, azithromycin
(penicillins, aztreonam, Linezolid
carbapenems)
Most quinolones Clindamycin
Vancomycin Metronidazole
Cotrimethoxazole Oxacillin, nafcillin, dicloxacillin
Daptomycin Ceftriaxone
Fluconazole Caspofungin
Voriconazole PO
Avoid use altogether Amphotericin b
Tetracycline
Nitrofurantoin (CrCl <40)
Voriconazole IV (CrCl<50)
Aminoglycosides (if possible)
Adverse Reactions to Antimicrobial
Agents
There are three general types of adverse
reactions to antimicrobial agents:
hypersensitivity reactions (which are not dose
related),
direct drug toxicity (which usually is dose
related and manifests in a single organ or,
occasionally, in several organs), and
microbial superinfection.
direct drug toxicity
to the kidney are aminoglycosides, polymyxins, and amphotericin B;
azotemia and renal tubular damage may be caused by any of these drugs.
Penicillins, cephalosporins, tetracyclines, and rifampin can cause
hemolytic anemia, thrombocytopenia, and leukopenia that involve an
immune mechanism, but these reactions are uncommon. Neutropenia can
occur during therapy with penicillins, cephalosporins, or vancomycin.
Macrolides and trimethoprim-sulfamethoxazole have been associated
with agranulocytosis.
Trimethoprim can produce anemia, leukopenia, and thrombocytopenia
from folate deficiency; the effect is reversible with folinic acid.
Amphotericin B commonly produces a reversible normocytic
normochromic anemia, probably secondary to injury to the red cell
membrane.
Flucytosine causes bone marrow suppression (leukopenia or
pancytopenia) when its excretion is reduced by renal failure.
Linezolid can also produce myelosuppression; although experience is
limited, bone marrow function usually recovers when the drug is
discontinued.
Reasons for failure of
chemotherapy .
1- wrong diagnosis
2- wrong choice of drug
3- wrong dose
4- development of resistance
5- infections with more than one organism
6- presence of pus, blood, necrotic tissues .
Duration of Antibiotic Therapy
Resolution of clinical parameters 27 VAP pts
Mean log CFU/mL White blood cell count x 103/L
7 17
6 16
5 15
4 14
3 13
2 12
1 11
0 10
-1 9
0 3 6 9 12 15 0 2 4 6 8 10 12 14 16
Antibiotic day Antibiotic day
Dennesen et al. Am J Crit Care Med 2001;163:13711375
Duration of Antibiotic Therapy
Resolution of clinical parameters 27 VAP pts
Highest temperature (C) PaO2:FiO2 ratio (KPa)
40 50
45
39 40
35
38 30
25
37 20
0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16
Antibiotic day Antibiotic day
Dennesen et al. Am J Crit Care Med 2001;163:13711375
Kapankah penggunaan ANTIBIOTIK
dikatakan berhasil?
setelah tiga hari terutama dilakukan
pemberian obat berdasarkan tampilan klinis
EVALUASI
Kriteria Klinis
ALIH TERAPI
tidak ada gangguan ANTIBIOTIK bebas demam
pada saluran cerna kurang lebih 2 hari
Fosfomicin
Antagonism Synergism Additive
Macrolides
Tetracyclines
Chloramphenicols
KOMBINASI ANTIBIOTIKA
Efek yang
Antimikroba Obat lain
tak diinginkan
Tetrasiklin Kalsium Absorpsi tetrasiklin
ber(-)
Gentamisin OAINS Efek samping
gentamisin ber(+)
Penisilin Probenesid Efek penisilin ber(+)