Prudent Antimicrobial Usage in

Daily Practice

Khie Chen

Division of Tropical Medicine and Infectious Diseases

Department of Internal Medicine
Medical Faculty University of Indonesia
Principles of Antimicrobial Therapy
 Selective toxicity is the ability to kill or inhibit
the growth of microorganism without harming
the cells of the host
 Reach the site of infection at inhibitory
concentrations
 Penetrate and bind to target
Appropriate antimicrobial usage

Underusage Appropriate Overusage

Increase Increase
mortality RESISTANCE
Prolonged Cost
hospital stay
 Emergence of antimicrobial resistance
- Increase use - AM resistance
- Over use Inappropriate - Collateral damage
- Misuse use - Increase morbidity/mortality
- Under use - Higher cost

Need AM policy to control AM usage!

Rational Usage
Prudent Usage
Responsible Usage of AM

Ref. WHO policy perspective on medicines: containing antimicrobial resistance.

WHO, Geneva, 2005
 Consideration When Choosing
an Antibacterial Agent
Outcome
Microbiology
 Clinical efficacy
 Mechanism of action
Concentration  Bacterial eradication
 Antibacterial spectrum
at infection site  Compliance with
Drug dosing regimen
 Tolerability
Pathogen MIC
PK  Rate of resolution
 Prevention of resistance
 Absorption PD
 Distribution
 Metabolism
 Time vs. concentration
 Excretion dependent killing
 Optimal dosing  Bactericidal vs. bacteriostatic
regimen activity
 Tissue penetration
(Scaglione, 2002)  Persistence of antibacterial effect
Underlying, comorbidity
Immune status
Severity/sepsis
Organ disfunctions
Underlying, comorbidity
Immune status
Severity/sepsis
Organ disfunctions

Gram positive/negative
Community/HCAI/HAI
Sensitive/Resistance
 Underlying, comorbidity
Immune status
Severity/sepsis
Organ disfunctions

Antibiotic spectrum Gram positive/negative

Availability Community/HCAI/HAI
Cost Sensitive/Resistance
 Cell wall synthesis
Protein synthesis
inhibition
inhibition

FOM Penicillins
Macrolides Aminoglycosides penicilin-G
(Fosfomycin)
erythromycin kanamycin ampicillin
midecamycin, dibekacin cloxacillin, etc.
amikacin Cephems
etc.
streptomycin cephalosporins
cephamycins
Chloramphenicol Tetracyclines
Inhibition of nucleic
acid synthesis
Cytoplasmic
membrane
DNA synthesis inhibition
inhibition
Quinolones
Polypeptides RNA synthesis inhibition
polymixin B, etc. rifampicin

CLASSIFICATION OF CHEMOTHERAPEUTIC
AGENTS BY MECHANISM OF ACTION
 1. Antibiotik yang bekerja pada
sintesis dinding sel
1. Cycloserine
2. Glikopeptida (vancomycin, teicoplanin)
3. Bacitracin
4. Beta-lactam (penisilin, sefalosporin,
carbapenem, monobactam)
Activity of Glycopeptides (cell wall active
agents) against common organisms

Gram (+)ve Gram (-)ve

Staphylo Strepto Entero Pseudo
Glycopeptides cocci cocci cocci E.coli monas
Vancomycin + + + R R
Teicoplanin + + + R R

• Large polar molecules, can only be given intravenously

• Are useful against MRSA
• Oral vancomycin is used to treat C. difficile (G (+)ve rod)
• Vancomycin is nephrotoxic, teicoplanin less so
Beta-lactam antibiotics
 Penicillins
 Cephalosporins
 Carbapenems
 Monobactams
 Cephamycins
Activity of ß-lactams against common organisms
Gram (+)ve Gram (-)ve
Staphylo Strepto Entero Pseudo
Penicillins cocci cocci cocci E.coli monas
Benzylpenicillin + + R R R
Flucloxacillin + + R R R
Amoxycillin + + + + R
Piperacillin + + + + +
Cephalosporins
Cephalexin + + R Urine only R
Cefuroxime + + R + R
Ceftriaxone R + R + R
Ceftazidime R + R + +
Carbapenems
Imi/Mero/Dori + + + + +
Beta-laktamase inhibitor
 Clavulanic acid
Combination with Amoxicilln
 Sulbactam
Combination with Ampicillin
 Tazobactam
Combination with Piperacillin
 2. Inhibition of protein synthesis
1. Aminoglycosida
2. Macrolide
3. Tetrasiklin
4. Chloramphenicol
5. Asam Fusidat
 Aminoglycosides
 Gentamicin First broad spectrum
 Tobramycin aminoglycoside
 Amikacin Similar spectrum to gentamicin
Semi-synthetic derivative of
kanamycin, active against
Gentamicin-resistant G(-)ve rods
• Neomycin Toxic- used topically

• Streptomycin Oldest aminoglycoside – now

used to treat TB
Aminoglycosides - spectrum of activity
Gram (+)ve Gram (-)ve
StaphyloStrepto Entero Pseudo
Drug cocci cocci cocci E.coli Klebsiella monas
Gentamicin + + + + + +
Amikacin + + + + + +
Streptomycin + + + + + +
Gram (+)ve wall
structure (stain with
difficulty)
Entero- Bacter-
M. tb MAI bacter Proteus oides
Gentamicin R + + + R
Amikacin + + + + R
Streptomycin + + + + R
 Macrolide
 Newer macrolides inhibit Mycobacteria,
protozoa (T. gondii, E. histolytica, P.
falciparum), Campylobacter, Helicobacter,
Borrelia, Neisseria & other genital pathogens
 GI complications, mostly with erythromycin
 Given orally, but absorbtion & bioavailability
variable from one macrolide to another
 Tetracyclines
 Active against many common Gram (+)ve &
(-)ve bacteria, chlamydiae, rickettsiae,
coxiellae, spirochaetes, some mycobacteria, E
histolytica, & plasmodia
 Given orally, absorbtion affected by food
 New generation Tygecycline given iv
 Effect on dentition (chelates Ca)
 GI intolerance (nausea) are common
 3. Sintesis asam nukleat:
 Menghambat sintesis prekursor
Sulphonamides
Trimethoprim
 Menghambat replikasi DNA
Fluorokuinolon
 Menghambat RNA polymerase
Rifampisin
 Klasifikasi Fluorokuinolon
GEN. Nama Aktivitas antibakterial
Gen I Nalidixic acid terutama terhadap
Enterobacteriaceae

Gen II Ciprofloxacin* terutama terhadap gram

Pefloxacin bakterik negatif & terbatas
Ofloxacin gram positif

Gen III Levofloxacin* ‘Broad spectrum’ aktif thd

Sparfloxacin gram neg & pos (Strep)
atypical,

Gen IV Gatifloxacin sama dg gen 3 +

Moxifloxacin anaerobes
Gemifloxacin
Clin Inf. Dis, 2000; 31:47- 82
* Cipro dan Levo memiliki efek antipseudomonas
 In Vitro Spectrum Activity of Antibiotics

Antibiotic Gram- Gram- Resistant Resistant Anaerobe Pseudo

negative positive Gram-negative Gram-positive
β-Lactam/
β-Lactamase
Inhibitor

3rd-generation
cephalosporins

Tigecycline

Glycopeptides

Carbapenems

Quinolones

Varies by product within class

In Vitro Activity

No In Vitro Activity
 Classification of antibiotic spectrum

 Gram positive/Gram negative

 Aerobe/anarobe
 Anti-Pseudomonal/non-pseudomonal
 Anti-MRSA/non MRSA
 Limited spectrum/broad spectrum
Limited Spectrum Therapy of HAP
 Enteric gram- Core antibiotics:
negative • Cephalosporin: 2nd generation
(non-pseudomonal) or non-pseudomonal 3rd
generation
 Enterobacter spp. • Beta-lactam/beta-lactamase
 E. coli inhibitor combination
 Klebsiella spp. • Ertapenem
 Proteus spp. • Fluoroquinolone (levofloxacin,
 S. marcescens moxifloxacin)*

 H. influenzae • Clindamycin+aztreonam *

 MSSA * PCN allergic

 S. pneumoniae
 Broad Spectrum Therapy of HAP
Aminoglycoside or Anti-Pseudomonal
Core Organisms Plus: Quinolone (Ciprofloxacin, High Dose
Levofloxacin) Plus:
 P. aeruginosa
• Anti-pseudomonal penicillin
 Acinetobacter
• Ceftazidime or cefoperazone; cefepime

• Aztreonam

• Imipenem, meropenem

• Beta-lactam/beta-lactamase inhibitor

(piperacillin/tazobactam)

Consider MRSA • ± Linezolid or Vancomycin

 Antibiotic classification in ASP
Class 1 Class 2 Class 3
Aminoglikosida Sefalosporin gen III Teicoplanin
Penisilin Fluorokuinolon Linezolid
Sefalosporin gen.I,II gen III-IV Sefepime
Kloramfenikol Amikasin Sefpirome
Asam fusidat Carbapenem
Lincosamid Tygecycline
Makrolida Seftasidime
Nitroimidazol Pip-Tazo
Fluorokuinolon Aztreonam
gen.I,II
Vancomisin
Tetrasiklin
TMP-SMX
Fosfomisin
Antibiotic usage in clinical practice
 Empirical treatment
 Definite treatment

 Prophylaxis
 Prinsip dalam Pemilihan Jenis
Antimikroba
 Bila mungkin, pilih antimikroba dengan spektrum
paling sempit kecuali pada infeksi berat atau sepsis.
 Infeksi yang berasal dari komunitas dapat dimulai
dengan antibiotik spektrum sempit, kecuali pada infeksi
yang didapat dari Rumah Sakit .
 Pasien dengan risiko tinggi terinfeksi patogen MDR,
dapat dipertimbangkan pemberian antibiotik spektrum
luas baik monoterapi ataupun kombinasi.
 Prinsip Pemilihan Antimikroba
pada Sepsis
1. Pilih antimikroba dengan spektrum luas terutama pada
sepsis berat dan renjatan septik baik monoterapi atau
kombinasi.
2. Berikan antibiotik segera dalam 6 jam diagnosis
ditegakkan. Pada renjatan septik diberikan dalam 1 jam.
3. Ambil kultur darah sebelum antibiotik diberikan
4. Evaluasi penggunaan antibiotik dengan marker biologis
(biomarker) bila mungkin : CRP atau PCT
5. Lakukan deeskalasi bila kultur sudah didapatkan
 Strategi Terapi Antimikroba Empirik
Pasien

Rawat jalan Rawat Inap

Kondisi stabil Infeksi berat/sepsis/risiko tinggi

Eskalasi Deeskalasi

Seleksi antibiotik sesuai

Pola kepekaan dan resistensi
Status imun, komorbiditas dan disfungsi organ

Terapi antibiotik monoterapi/kombinasi

Pohan HT, 2005
 Principles of Empirical Antimicrobial
Selection
 Define the diagnosis and site of infections
: LRTI, UTI, cIAI, cSSTI, others
 Stratified the patient conditions :
- Disease severity
- Risk factors
 Know the local susceptibility data and incidence of
resistance pathogens
 Collect the sample for microbiological culture
 Choose the empirical antibiotics treatment :
monotherapy or combinations
 Reassess Therapy by Day 3-5
 Review the diagnosis, follow up the progress
 Use biomarkers (CRP or PCT) if available

 Review the microbiological resuts :

Gram stain, positive culture

 Plan to de-escalate the antimicrobial to narrow
spectrum based on drug of choice for selected organism
eg. Pseudomonas aeruginosa, Acinetobacter sp , ESBL
MRSA, etc.
 De-escalation approach to antimicrobial utilization
Serious hospital acquired infection suspected
Obtain appropriate microbial
sample for culture and special stain

Begin empirical antibacterial treatment with

a combination agents targeting the most common
pathogen based on local data

Follow clinical parameter : Temp, WBC, CXR

PaO2/FiO2, haemodynamic, organ function

De-escalating antibacterial based on

results of clinical microbiology data

Search for superinfection

Abscess formation N Significant clinical improvement
Non infectious caused after 48-96 hours
of fever
Y
Discontinue antibacterial after 7-14 days course based
on site of infection and clinical response

Kollef, Drugs 2003;63 (20): 2157

 De-escalation of antibiotics
 Definite pathogen could be identified
 Clinically (and laboratory) improvement
 Availability of narrower spectrum antibiotics
(for certain pathogen)
 Beware to deescalate in case of colonization
and in high risk patients for antimicrobial failure
 Non responder patients
 Evaluation for diagnosis : non infection cause :
pulmonary emboli, atelectasis, malignancy
 Multi drug resistance pathogen not covered by provious
antibiotics
 Non bacterial cause of infections : viral (eg CMV) or
fungals
 Focal site infections not adequate manage
infected CVC, abscess, intraabdominal site infection
 Escalation of antimicrobial

 Change to broader spectrum antibiotics

 Combine with other antibiotics
 Increased dosage
 Modify drug delivery
 Antibiotics for definite pathogens

1. Pseudomonas aeruginosa
2. Methicillin-resistant Staphylococcus aureus
3. Acinetobacter species
4. Extended spectrum β-lactamase-producing
Klebsiella, E coli, Enterobacteriadeae

American Thoracic Society. Guidelines for the management of adults with hospital-acquired,
ventilator-associated and healthcare-associated pneumonia. Am J Respir Crit Care Med.
2005;171:388–416
 Antimicrobial Treatment based on
Microbiological Culture Results
Microbiological culture results

Colonization Pathogen

No treat Sensitive Resistant

Treat with Antibiotics Optimized

Recommended Combination PKPD
Antibiotics
Antimicrobial Treatment for
MRSA
Glycopeptide : Vancomycin, Teicoplanin
Oxazolidinones : Linezolid
Streptogramin : Quinopristin-Dalfopristin
Gycylcycline : Tygecyclin
Alternative : Cotrimoxazole, Minocycline,
Fluoroquinolones
Rifampicin
Combination treatment :
Cotrimoxazole + Rifampicin
Minocyclin + Rifampicin
 Antimicrobial treatment for
Pseudomonas aeruginosa
Isolate significant :
CSF (NP), Blood (P), Sputum (C/P)
Urine (C/P), Stool (NP), Wound (C)
Monotherapy :
Meropenem, Imipenem, Doripenem
Cefepime
Aztreonam
Combination therapy :
Piperacillin/Tazobactam
Meropenem, Imipenem, Doripenem
Cefepime
+ Amikacin
Antimicrobial treatment for Acinetobacter
baumaii/iwanofii/ coloaceticus
Isolate significant :
CSF (C/P), Blood (P), Sputum (C/P)
Urine (C/P), Stool (NP), Wound (C)
Prefered therapy :
Ampicillin Sulbactam
Piperacillin Tazobactam
Imipenem, Meropenem, Doripenem
Tygecycline
Alternative therapy :
Colistin (MDR)
Polimyxin (MDR)
Cefepime
 Treatment options for MDR Acinetobacter

Carbapenem is the choice of therapy for

Acinetobacter
 Consider colistin/polymixin for carbapenem –
resistant Acinetobacter
 Consider Tigecycline as part of a combination
regimen
Antibiotic options for ESBL-producing GN bacilli
Antibiotic Fact Recommendation
3rd generation
Documented clinical failures No
cephalosporins
4th generation
Inoculum effect No
cephalosporins
-lactam /
-lactamase Variable in vitro and in vivo efficacy No
inhibitor
Frequent coexistence of FQ
Fluoroquinolones No
resistance
Not for serious
Cephamycin ESBL producers with AmpC
infections
Carbapenems Best clinical efficacy Yes
Tigecycline In vitro active
Eccmid 2011
Adequate dosing regimen in severe infections

 Ciprofloxacin: 400 mg q8h; Levofloxacin 750 mg qd

 Imipenem 1000 gm q 8H or 500 mg q 6h; Meropenem
1000mg q 6-8 h, Doripenem 500-1000 mg q 8h
 Piperacillin/Tazobactam 4.5 g q 6h
 Cefepime 2 g q 8-12h
 Ceftazidime 2 gm q 8h
 Gentamicin or Tobramycin 7 mg/kg / day or
Amikacin 20 mg/kg/day
 Linezolid 600 mg q 12 h
 Vancomycin 15 mg/kg q12h
 Optimizing the PKPD profile of Antibiotics
Cmax = Peak Concentration Dependent
Cmax / MIC AUC / MIC
Aminoglycosides1,2 Aminoglycosides2
Fluoroquinolones1,2 Fluoroquinolones1,2
Oxazolidanones1,2
Glycopeptides2
Concentration

Lincosamides2
Lipopeptides1,2
Tetracyclines2
Macrolides2
MIC
Penicillins1
Cephalosporins1 T > MIC
Carbapenems1 Cmin = Trough
Macrolides1,2
Glycopeptides2
Lincosamides2
Time (hours)

1. Nicolau DP. J Infect Chemother. 2003;9:292-296.

2. Ambrose PG, et al. Clin Infect Dis. 2007;44:79-86.
Faculty of Medicine University of Indonesia Dr. Cipto Mangunkusumo General Hospital
Jakarta, Indonesia Jakarta, Indonesia.