Dept.

Pharmacology & Therapeutic

School of Medicine
Universitas Sumatera Utara
 etc, fever
etc,etc cough
etc
anti-
crying cipro
penem
microbial
agents
dyspnea

anxiety diarrhea
insomnia
 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

Tidak Sakit Karier

sakit
Penyakit infeksi
 Manifestation of Infection
Local Inflammation Systemic Inflammation
initial and sometimes fatigue,
final response malaise,
What is observed? anorexia,
wound margins myalgia,
exudates
arthralgia, and
sensations
skin temperature fever
 Signs & Symptoms of Infection
Fever
Increased white blood cell count (WBC)
Redness, warmth, swelling, tenderness
Purulent drainage
 Mortality rate associated with initial inadequate therapy for
critically ill intensive care unit patients with serious infections

*Mortality refers to crude or infection-related mortality. **Includes

Niederman patients
M S Clin Infect Dis.with HAP.
2006;42:S72-S81
***Patients had blood stream infections rather than pneumonia as in the other studies.
Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.; Luna CM et al. Chest 1997;111:676-685.; Rello J et al. Am J Respir Crit
Care Med 1997;156:196-200.; Kollef MH et al. Chest 1998;113:412-420.; Ibrahim EH at al. Chest 2000;118:146-155.; Harbarth S et al.
Am J Med 2003;115:529-535. & Valles J et al. Chest 2003;123:1615-1624.
 Pertimbangan Pemilihan
Antibiotik

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

Abdomen Urinary Tract Upper Respiratory

E. coli, Proteus E. coli, Proteus S. pneumoniae
Klebsiella Klebsiella H. influenzae
Enterococcus Enterococcus M. catarrhalis
Bacteroides sp. Staph saprophyticus S. pyogenes

Lower Respiratory Lower Respiratory Meningitis

Community Hospital S. pneumoniae
S. pneumoniae K. pneumoniae N. meningitidis
H. influenzae P. aeruginosa H. influenza
K. pneumoniae Enterobacter sp. Group B Strep
Legionella pneumophila Serratia sp. E. coli
Mycoplasma, Chlamydia S. aureus Listeria
 Choice of an antibiotic

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

mengukur konsentrasi obat yang diperlukan untuk

menghambat perkembangan atau membunuh organisme
tersebut
 Classification of Antibiotics
Bacteriostatic Bactericidal
 Bateriostatic vs bactericidal
Bacteriostatic: agents that arrest the
growth and replication of the bacteria
Bactericidal:agens that kill bacteria
In seriously ill pts we choose bactericida
agents rather than static
Some agents are bacteriostatic to one and
bactericidal for the other
Example :chloramphenicol is static against G-
ve rods and cidal for S.pneumonia
 According to spectrum
1- Narrow spectrum as penicillins ,
aminoglycosides

2- Broad spectrum as tetracyclines ,

chloramphenicol
 Chemotherapeutic spectrum
Narrow spectrum
Effective against single or limited group
Example :isoniazide
Extended spectrum
Effective against gram positive and some gram negative
Example :ampicillin
Broad spectrum
Affect a wide variety of microbial species
Affect the nature of normal flora
Precipitate superinfection
Example:tetracyclin,chloramphenicol
 Frambusia = YAWS
Yaws is the most prevalent infectious,
nonvenereal treponemal disease and is
caused by Treponema pallidumpertenue.
Penicillin is the drug of choice for yaws.
After a single penicillin injection, early
lesions become noninfectious after 24
hours and heal within 1-2 weeks.
Tetracycline, erythromycin, or doxycycline
should be considered for patients allergic
to penicillin
The tree of antibiotics
Bacterial Targets for Antibiotics
 Antimicrobial Resistance:
Key Prevention Strategies
Susceptible
Antibiotic
Pathogen
Pathogen
resistant pathogen
Prevent Prevent
transmission infection

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

Craig WA. Pharmacokinetic/pharmacodynamic parameters:

Rationale for antibacterial dosing of mice and men. Clin Infect Dis. 26:112,1998
Depiction of pharmacodynamic parameters
over a concentration-time profile

Time above MIC

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

Area under the curve AUC/MIC is the

ratio of the AUC
concentration

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

8 Drug A Time above MIC

Antibiotic concentration

Proportion of the
6 dosing interval
Drug B
(ug/ml)

when the drug

4
concentration
exceeds
2 MIC
B the MIC
A
0
Time above MIC
Time
 Concentration vs. time-dependent
killing agents
Concentration dependent agents:
bacterial killing as the drug concentrations
exceed the MIC
Peak/MIC (AUC/MIC) ratio important
Quinolones, aminoglycosides
Time-dependent agents: kill bacteria when
the drug concentrations exceed the MIC
Time>MIC important
Penicillins, cephalosporins
 Pharmacodynamics of Bacterial Killing
Concentration-dependent (greater bacterial kill at higher concentrations)
vs. Concentration-independent (time dependent)
antibiotics can be divided into
3 categories
Pattern of Activity Antibiotics Goal of Therapy PK/PD Parameter
Concentration-
Aminoglycosides Maximize
dependent killing 24h-AUC/MIC
Daptomycin concentrations
and
Fluoroquinolones
Prolonged Single daily dose Peak/MIC
Ketolides
persistent effects
Carbapenems Maximize duration
Time-dependent
Cephalosporins of exposure
killing and
Erythromycin T>MIC
Minimal persistent Multiple DD or
Linezolid
effects continuous infusion
Penicillins
Time-dependent Azithromycin Maximize amount
killing and Clindamycin of drug
Moderate to Oxazolidinones 24h-AUC/MIC
prolonged Tetracyclines Total dose and
persistent effects. Vancomycin duration
 Once-daily vs. Conventional Three-times Daily
Aminoglycoside Regimens Optimizes Concentration-
dependant Effect on Bacterial Kill

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)

10.0 Extended Infusion (3 h)

1.0
MIC
Additional T>MIC gained
0.1
0 2 4 6 8
Time (h)

Dandekar PK et al. Pharmacotherapy. 2003;23:988-991.

Steady-state clarithromycin plasma
concentration time profiles
 An appropriate use of antibiotics is the only way
to obtain an optimal therapeutic effect
Beside defining the pathogenic microorganism,
the way of antibiotic administered determin its
efficacy, ie. time or concentration dependent.
For time dependent antibiotic, its efficacy will
enhance by optimising duration of exposure, ie.
frequent adminstration,
extended release formulation or
extended infusion.
 Major route of elimination
Hepatobiliary Renal
Choloramphenicol Most beta lactams
Doxycycline Aminoglycoside
Moxifloxacin TMP-SMX
Macrolides Carbapenems
Nafcilin Polymyxin
INH Tetracycline
PRZ Vancomycin
Rifampin Most quinolones
Clindamycin Nitrofurantoin
Metronidazole
 Dosing Adjustments in Renal Disease?

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

parameter laboratoris : hitung

menilai
leukosit, pemeriksaan kultur dan
kegagalan terapi
resistensi
 Successful treatment outcomes
Temperature returns to normal
Symptoms improve
Signs of infection resolve
White blood cell counts normalize
Cultures become negative
 Administration
Schedule at regular intervals to maintain
steady blood levels
Assess allergies prior to administration
Monitor for adverse and therapeutic effects
Drug interactions
Importance of completing full course
IV therapy changing to oral
Patient education
Antibiotic Cyt.P-450 Related Interactions
Inhibits Cyt.P-450:
Anticoagulants oral -- hypoprothromb.>
Erythromycins Carbamazepine toxicity -- >
Cisapride --Ventric. Arrhytmia
Fluconazole Digoxin bl.levels -- >>

Itraconazole Dilantin bl.levels -- <

Terfenadine -- Ventric. Arrhytmia
Ketoconazole Theophylline bl.levels -- >
Valproate bl.levels -- >

Induces Cyt. P-450: Anticoagulants -- hypothrombinaeia <

Rifampicin Chloramphenicol levels -- <

Contraceptives levels -- <
Corticoster. levels -- <
Cyclosporine levels -- <
 Mengganti ANTIBIOTIK?

tidak adanya indikasi tidak ada indikasi untuk

lanjutan diberikannya konsentrasi antibiotik di
antibiotik intravena jaringan

Kriteria Klinis
ALIH TERAPI
tidak ada gangguan ANTIBIOTIK bebas demam
pada saluran cerna kurang lebih 2 hari

adanya perubahan leukosit, hitung

jenis dan protein fase akut ke arah
normal
 Pertimbangan Penggunaan
ANTIBIOTIK Kombinasi
Terapi spektrum luas pada pasien-pasien
sakit parah
Mengobati infeksi polimikroba
Mengurangi munculnya strain resisten
Mengurangi toksisitas terkait dosis
Mendapatkan peningkatan penghambatan
atau pembunuhan bakteri
 KOMBINASI ANTIBIOTIKA
SINERGIS
Penisilin (amoksisilin) + aminoglikosida (gentamisin)
Amoksisilin + asam klavulanat
Sulfametoksazol + trimethoprim
Kloramfenikol + trisulfa
ANTAGONIS
Penisilin (bakterisid) + tetrasiklin (bakteriostatik)
Penisilin + aminoglikosida
[dalam satu wadah/spuit]
 drug interaction
Synergism
Penicillins Aminoglycosides
Cephalosporins Colistine
Synergism Synergism

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(+)

Sulfonamida NaHCO3 Kejadian kristaluria

ber(-)
 KESIMPULAN
ANTIMIKROBA bukan ANTIPIRETIKA
ANTI-TUSIVA
ANTI-DIARE
ANTI-ANXIETY
ANTIMIKROBA hanya diberikan bila terbukti atau disangka
kuat ada proses INFEKSI (kuman, jamur, virus, protozoa)

ANTIMIKROBA TUNGGAL lebih baik daripada

ANTIMIKROBA KOMBINASI
Waspada terhadap interaksi ANTIMIKROBA dengan
OBAT LAIN
Antibiotic Class Review