Pendidikan:Dokter Umum FKUY 1989Spesialis Penyakit Dalam FKUI 2003Institute of Tropical Medicine Prince Leopold, Antwerpen, Belgium 2005Fellow of Indonesian Society of Internal Medicine 2009Konsultan Penyakit Tropik & Infeksi FKUI 2013

Pekerjaan:Ka.SMF Penyakit Dalam RSPI Sulianti Saroso, 2014-sekarang Ketua Komite PPRA RSPI Sulianti Saroso 2015-sekarangPembimbing Klinik Residen Divisi Penyakit Tropik & Infeksi, Departemen Ilmu Penyakit Dalam FKUI, 2006-sekarangPembimbing Klinik Mahasiswa FK Untar, 2005-sekarangKoordinator Bidang Pelayanan Pokja HIV-AIDS RSPI-SS, 2004-2015Ketua Komite PPI RSPI-SS, 2004-2014

Organisasi:Ketua Perhimpunan Pengendalian Infeksi Indonesia (PERDALIN JAKARTA), 2016-sekarangAnggota Perhimpunan Konsultan Penyakit Tropik dan Infeksi Indonesia (PETRI), 2006-sekarang

Dr. H. I. Firmansyah, SpPD, KPTI, FINASIM

KEY POINTS

• Resistant bacterial strains are selected in hospitals due to huge usage of antibiotics

• To preserve the susceptibility of microorganism, and postpone the development of resistance, antibiotics should be used rationally

• If resistant bacteria develop in an environment where the specific antibiotic used, they will become prevalent in that environment

• Good antibiotic prescribing practices should be encouraged within hospitals

• The microbiology laboratory service can asisstclinicians to use targeted antibiotic treatment for patients

1. Mendes RE, et al. Antimicrob Agents Chemother. 2013 Nov;57(11):5721-6

Antibiotic-Resistant Species in Asia Pacific1

• National data throughout South East Asia and the Western Pacific shows alarming rates of resistance

Type of infection Area National data (% resistant)

E. coli resistant to 3rd

generation cephalosporins

South East Asia 16–68

Western Pacific0–77

E. coli resistant to fluoroquinolones

South East Asia 32–64

Western Pacific 3–96

K. pneumoniae resistant to 3rd generation cephalosporins

South East Asia 34–81

Western Pacific 1–72

E. coli, Escherichia coli; K. pneumoniae, Klebsiella pneumoniae

1. WHO Antimicrobial Resistance: Global Report on Surveillance 2014. Available from:

http://www.who.int/drugresistance/documents/surveillancereport/en/ Last accessed 07 May 2015.

Prevalence of Multi-drug Resistant Pathogens is High in Asia Pacific

• The prevalence rates of multidrug-resistant pathogens in Asia is high.

• These pathogens include:

– multi drug-resistant gram-negative bacilli3

– methicillin-resistant Staphylococcus aureus (MRSA)2

• Asia is among the regions with the highest prevalence rates of healthcare-associated methicillin-resistant S. aureus (HA-MRSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in the world1

– Β-lactam and macrolide-resistant Streptococcus pneumoniae2

AreaPrevalence of MRSA among

S. aureus isolates, %

Hong Kong1 28

Indonesia1 28

South Korea1 73

India2 45

Australia2 26

HA-MRSA, healthcare-associated methicillin-resistant S. aureus; CA-MRSA, community-associated methicillin-resistant S. aureus

1.Chen CJ, Huang YC. Clin Microbiol Infect. 2014;20:605-23

2.Mendes RE. Antimicrob Agents Chemother. 2013 Nov;57:5721-6

3.Kang CI, et al. Infect Chemother 2013;45:22-31

Antibiotic Over-Prescription Impacts Resistance11

1.Teng CL. Malays Fam Physician. 2014; 9:18-25.

Country Author, year of

publication

Setting Pts or prescriptions

(n)

(%) Antibiotic

prescribing rate

Australia Pan 2006 General practice 2,088 40 (Adults)

24 (Children)

China Jiang 2012 Township 3,059 85

Hong Kong Kung 2014 Public 895,978 5

Japan Higashi 2009 Outpatient 2,577 60

Korea Park 2005 Outpatient 16,736 81

Indonesia Marjadi 2009 Outpatient 6,804 70 (Public)

47 (Private)

Malaysia Fozi 2013 Outpatient 22,328 34

New Zealand Kljakovic 2005 General practice 335 61

Taiwan Hou 2014 Outpatient 6,915,140 6

Thailand Issarachaikul 2013 Outpatient 339 81

ANTIBIOTIC GUIDELINES

• Demonstrate a commitment to rational and prudent use of antibiotics

• Policies should focus on using antibiotics with the narrowest spectrum, which are cheap, have minimal toxicity and have the least impact on development of resistance

MRSA, methicillin-resistant Staphylococcus aureus

1. . Song JH. Antimicrobial Resistance Control 2015. Available from http://www.globalhealthdynamics.co.uk/wp-content/uploads/2015/05/06_Song.pdf. Accessed 08 June 2015.

2. Teng CL. Malays Fam Physician. 2014; 9:18–253. Chen CJ, Huang YC. Clin Microbiol Infect. 2014;20:605-23

4. Mendes RE. Antimicrob Agents Chemother. 2013 Nov;57:5721-65. Kang CI, et al. Infect Chemother 2013;45:22-31

Image source: © James Thew

Antimicrobial Resistance

9

• Inappropriate use, poor drug

quality and patient non-

compliance with therapy all

contribute to thedevelopment

of antimicrobial resistance1

• There are several multi-drug resistant pathogens (such as

MRSA and multi-drug resistant gram negative bacilli) which are

a significant issue and present in both the hospital and

community setting2–5

Antimicrobial Resistance 1

101. Sharfstein J. Testimony on Preservation of Antibiotics for Medical Treatment Act. Available from:

www.hhs.gov/asl/testify/2009/07/t20090713a.html. Accessed 20 Mar 2014.

Image source: © World Health Organization; used with permission

• …occurs when bacteria change in some way that reduces

or eliminates the effectiveness of drugs, chemicals or other

agents designed to cure or prevent infections

The ability of bacteria to resist the effects of a drug

1. Mulvey MR, Simor AE. CMAJ 2009;180:408-15.

How Do Antibiotics Acquire

Resistance?*

Antibiotic Targets Antibiotic Resistance

Cell Wall

β-lactams

Vancomycin

DNA/RNA Synthesis

Fluoroquinolones

Rifamycins

Folate Synthesis

Trimethoprim

Sulfonamides

Cell Membrane

Daptomycin Protein Synthesis

Linezolid

Tetracyclines

Macrolides

Aminoglycosides

Inactivating Enzymes

β-lactams

Aminoglycosides

Macrolides

Rifamycins

Immunity & Bypass

Tetracyclines

Trimethoprim

Sulfonamides

Vancomycin

Efflux

Macrolides

Fluoroquinolones

Aminoglycosides

Tetracyclines

β-lactams

Target Modifications

Macrolides

Fluoroquinolones

Rifamycins

Vancomycin

Penicillins

Aminoglycosides

This mechanism results in low- to mid-level resistance3

The efflux mechanismaccounts for more that2/3 of resistant isolates

This mechanism

resultsin high-level

Macrolide resistance

11

* Antibiotic targets and mechanisms of resistance. There are five major antibiotic targets: the bacterial cell wall, the

cell membrane, protein synthesis, DNA and RNA synthesis, and folic acid (vitamin B9) metabolism. Resistance to

antibiotics occurs through four general mechanisms: target modification; efflux; immunity and bypass; and enzyme-

catalyzed destruction

By Drug Inactivation or Modification1

12

• Bacteria can produce enzymes that modify or destroy the

chemical structure of the antibiotic

• The most common resistance-producing enzymes are the

β-lactamases

– Hydrolyse the β-lactam ring of penicillins, cephalosporins and carbapenems

• Two important β-lactamase subfamilies, primarily

responsible for causing resistance in Gram-negative

bacteria):

– Carbapenemases

• Metallo-β-lactamases (IMP, VIM, NDM-1), oxacillinase (OXA) and

Klebsiella pneumoniae carbapenemase (KPC) are among the most

important subtypes

– Extended-spectrum β-lactamases (ESBLs)

• TEM, SHV, CTX-M and OXA are the most common gene mutations

producing resistance

1. Mulvey MR, Simor AE. CMAJ 2009;180:408-15.

By Altering the Target Site1

13

• Antimicrobial efficacy is dependent on site-specific binding to, or within, the target pathogen

– The site varies between drug classes

• Resistance occurs when the pathogen changes the structureof the target

– Either prevents binding or reduces binding affinity

• Example: altered binding proteins in cell wall– Organisms: Streptococcus pneumoniae, MRSA

– Antibiotics affected: penicillin, methicillin, cloxacillin

• Example: altered DNA gyrase or topoisomerase– Organisms: S. pneumoniae, Pseudomonas aeruginosa,

Enterobacteriaceae

– Antibiotics affected: ciprofloxacin, levofloxacin, moxifloxacin

MRSA, methicillin-resistant Staphylococcus aureus

1. Mulvey MR, Simor AE. CMAJ 2009;180:408-15.

By Decreasing Drug Accumulation1

14

• To be effective, antimicrobials must achieve adequate concentrations at

their target sites

• There are two mechanisms by which pathogens prevent this:

– Decreased permeability

• Arises from mutations in genes coding for porins – outer membrane proteins that

allow diffusion of molecules into the bacterial cell

– Increased drug efflux

• Occurs where pathogens have evolved an active efflux mechanism that pumps

drugs out of the cytoplasm before they can bind to their target

• Some pumps are specific for a single drug class, others are multidrug resistant

• Example: change in outer membrane porins

– Organisms: Enterobacteriaceae, P. aeruginosa

– Antibiotics affected: gentamicin, tobramycin

• Example: efflux pump

– Organisms: S. aureus, streptococci

– Antibiotics affected: tetracycline, clindamycin, erythromycin

1. Mulvey MR, Simor AE. CMAJ 2009;180:408-15.

By Altering Metabolic Pathways

• Another resistance mechanism

used by bacteria is the bypass

of steps previously inhibited

by antibiotics1

– e.g. sulphonamides are chemical

competitive analogs of para-

aminobenzoic acid (PABA), and

inhibit folic acid and nucleic acid in

bacteria2

– Resistant bacteria avoid the need

for the PABA pathway by using

preformed folic acid instead2

Bypass Pathways

A + B AB

151. Coates A, et al. Nature Rev Drug Discovery 2002;1:895-910.

2. Sulfadiazine Tablets USP. Drugs.com. Available from: http://www.drugs.com/pro/sulfadiazine.html?printable=1. Last accessed 25 Apr 2014.

Gram-Positive and Gram-Negative

Organisms Develop Resistance

16

1. Huttner A, et al. Antimicrob Resist Infect Control 2013;2:31.

• Although resistance in Gram-positive organisms is

familiar, resistance among Gram-negative bacteria

is growing1

Resistant Gram-positiveorganisms, including…

S. aureus

Enterococcus faecium

Enterococci

Clostridium difficile

Resistant Gram-negativeorganisms, including…

Enterobacteriacae

Acinetobacter spp.

Klebsiella spp.

P. aeruginosa

Escherichia coli

Burkholderia cepacia

Proteus mirabilis

Neisseria gonorrhoeae

Who Should Prescribe Antibiotics?

171. CDC. Antibiotics Aren’t Always the Answer. Available from: www.cdc.gov/features/getsmart/. Accessed 8 Apr 2014.

2. WHO Fact Sheet. Rational Use of Medicines. Available from: www.who.int/mediacentre/factsheets/fs338/en/. Accessed 8 Apr 2014.

• Antibiotics are prescription medicines

– Antibiotics should only be used when a doctor determines

that they are needed to treat a bacterial infection1

• Antibiotics need to be prescribed by a doctor

– No other healthcare professionals should provide or

dispense antibiotics without a doctor ’s prescription

• Distribution of antibiotics by anyone other than a

doctor leads to problems, such as overuse,

inappropriate self-medication and use of the wrong

dosage2

Antibiotic Prescription in the Community

181. Suda KJ, et al. J Am Pharmacist Ass 2012;52:6-10.

2. NICE Clinical Guideline 69

Image source: © KOUNADEAS IOANNHS

• The majority of antibiotic prescriptions in the outpatient

setting are for upper respiratory tract infections (URTIs)1

– Ear infection, sinusitis, pharyngitis, sore throat, coughs/colds

• However, not all need to be treated immediately with

antibiotics2

• Depending on clinical assessment of severity, a no

antibiotic or delayed antibiotic prescribing strategy is

recommended for adults or children with:2

– Acute ear infection

– Acute sore throat, pharyngitis or tonsillitis

– Common cold

– Acute rhinosinusitis

– Acute cough or bronchitis

When a Doctor May

Prescribe Antibiotics1

URTI, upper respiratory tract infection

1.CDC Adult Appropriate Antibiotic Use Summary. Available from:

www.cdc.gov/getsmart/campaign-materials/info-sheets/adult-approp-summary.pdf. Accessed 18 Mar 2014.

Non-specific upper respiratory tract infections (adult)

• Non-specific URTIs or acute rhinopharyngitis, in the

absence of sinus, pharyngeal and lower airway

symptoms, are typically VIRAL in origin1

• Antibiotic treatment is NOT RECOMMENDED1

– Antibiotics do not enhance illness resolution or prevent

complications

• Purulent secretions are common in patients with

URTIs, but do not predict bacterial infection or benefit

from antibiotic treatment1

42

Acute pharyngitis (adult)

• The aetiological agent in ≈10% cases of pharyngitis is Group

A beta haemolytic streptococcus (GABHS)

• Acute pharyngitis is self-limiting in the large majority of

adults, who need SUPPORTIVE CARE ONLY

• Limit antibiotic prescription to patients most likely to have

GABHS infection

– History of fever, tonsillar exudates, absent cough, lymphadenitis

– Penicillin or amoxicillin preferred

– Treat for 10 days

– First-generation cephalosporin, clindamycin, clarithromycin or

azithromycin in penicillin-allergic patients

.

43

1. CDC Adult Appropriate Antibiotic Use Summary. Available from: www.cdc.gov/getsmart/campaign-materials/info-sheets/adult-approp-summary.pdf. Accessed 18 Mar 2014.

2. Shulman ST, et al. Clin Infect Dis 2012;55:1279–82.

When a Doctor May

Prescribe Antibiotics1

When a Doctor May

Prescribe Antibiotics1,2

1. CDC Adult Appropriate Antibiotic Use Summary.

Available from: www.cdc.gov/getsmart/campaign-materials/info-sheets/adult-approp-summary.pdf. Accessed 18 Mar 2014.

2. Chow AW, et al. Clin Infect Dis 2012;54:1041-5

Rhinosinusitis (adult)

• Diagnose acute bacterial rhinosinusitis if:

– Symptom duration ≥7 days; maxillary facial/tooth pain or

tenderness are present; purulent secretions are evident

• Resolves WITHOUT ANTIBIOTIC TREATMENT in the

majority of cases

• Reserve antibiotics for patients with moderate-to-severe

symptoms

• Initiate empiric antibiotic treatment with the most

narrow-spectrum agent active against the likely

pathogens

44

When a Doctor May

Prescribe Antibiotics1

1. CDC Adult Appropriate Antibiotic Use Summary. Available from: www.cdc.gov/getsmart/campaign-materials/info-sheets/adult-approp-summary.pdf. Accessed 18 Mar 2014.

Bronchitis (adult)

• Focus on ruling out pneumonia in adults with an

acute cough illness

– Pneumonia is uncommon in the absence of vital sign

abnormalities or asymmetrical lung sounds

• Routine antibiotic treatment of uncomplicated

bronchitis is NOT RECOMMENDED

– In the unlikely event pertussis is suspected, perform a

diagnostic test and initiate antibiotics

45

When a Doctor May

Prescribe Antibiotics1

CAP, community-acquired pneumonia

1. Mandell LA, et al. Clin Infect Dis 2007;44(Suppl.2):S27-72.

Community-acquired pneumonia (adult)

• Initial empirical antibiotic therapy is recommended

– A macrolide (azithromycin, clarithromycin or erythromycin) (or

doxycycline) in previously healthy outpatients with no risk factors

for drug-resistant S. pneumoniae

• When the infection aetiology has been determined,

pathogen-directed antibiotic therapy is appropriate

• Treatment duration typically ≥5 days for most antibiotics

‒ Some antibiotics, such as azithromycin, require a shorter course

‒ Patients need to be afebrile for 48–72 hours and have

≤1 CAP-associated sign of clinical instability before antibiotic

therapy is discontinued

46

When a Doctor May

Prescribe Antibiotics1,2

1. Fujimoto T. Japan Med Ass J 2009;52:158–63.

2. NICE Clinical Guideline 69.

Ear infection

• Infection resolves spontaneously in 80% of patients1

• A no antibiotic or delayed antibiotic prescribing

strategy is recommended1,2

• Observe for 3 days after symptom onset1

• Start empirical antibiotic therapy after 3 days in

patients who fail to improve or who have more severe

symptoms1

47

When a Doctor May Prescribe

Antibiotics: Special Patient Groups

25RTI, respiratory tract infection

1. NICE Clinical Guideline 69

• In patients with RTIs, immediate antibiotic prescription

and/or further investigation and management should be

offered in the following situations:

– The patient is systemically very unwell

– Signs/symptoms of serious illness and/or complications are present

– When pre-existing co-morbidity puts the patient at high risk of

serious complications

– Acute cough and patient age >65 years with ≥2 of the following or

>80 years and ≥1 of the following:

• Hospitalisation in previous year

• Type 1 or type 2 diabetes

• History of congestive heart failure

• Current use of oral glucocorticoids

CONCLUSION

• Every hospital should make the AB guidelines for empirical treatment

• Implementing of AB guidelines should be done through continuing workshop

• Measuring of AB effectiveness based on local guidelines should be done periodically based on pharmacologic and microbiologic site

ight drug

ight time

ight dose

ight duration

+Infection

ControlRRIGHT DIAGNOSIS

Successful Antibiotic Therapy