CLINICAL PHARMACOLOGY ASPECT OF ANTIBIOTIC USAGE IN HOSPITALIZED PATIENTS

Danny Suwandi Department of Pharmacology & Therapeutics Faculty of Medicine Hasanuddin University

Top 10 Causes of Death in the World

Coronary heart disease (12.2%) Stroke and other cerebrovascular diseases (9.7%) Lower respiratory infections (7.1%) Chronic obstructive pulmonary disease (5.1%) Diarrheal diseases (3.7%) HIV/AIDS (3.5%) Tuberculosis (2.5%) Trachea, bronchus, lung cancers (2.3%) Road traffic accidents (2.2%) Prematurity and low birth weight (2%)

Perkembangan terapi antibiotika dalam 7 dasawarsa terakhir ini sangat pesat, tetapi angka morbiditas/mortalitas penyakit infeksi tetap tinggi Masalah :
1. Pemilihan antibiotika makin beragam 2. Penggunaan antibiotika cenderung tidak rasional Resistensi 3. Biaya kesehatan meningkat

Strategi :
Pemahaman mengenai : 1. Klasifikasi anti-infeksi/antibiotika 2. Dasar-dasar penggunaan 3. Akibat serta penanggulangannya

Setiap antibiotika tidak menjamin dapat digunakan pada setiap infeksi

Conventional Antibiotics

Penicillin Cephalosporin Carbapenems Quinolones Aminoglycosides Macrolides Tetracycline Nitrofurantoin, Metronidazole, clindamycin, vancomycin, teicoplanin, cotrimoxazole, fusidic acid, etc. Isoniazid, pyrazinamide, ethambutol, rifampicin, cycloserin, etc.

Prinsip Pemilihan & Pemakaian Antibiotika Dalam Klinik

Terapi secara EMPIRIS

Berdasarkan perkiraan (educated guess) Pola epidemiology kuman setempat

Terapi secara pasti (DEFINITIF) :

Berdasarkan hasil pemeriksaan mikrobiologis Jenis kuman Spektrum kepekaan

Terapi Profilaksis (PREVENTIF)

Penderita yang sering terpapar pada mikro organisme tertentu untuk mencegah terjadinya infeksi oleh mikro organisme tersebut Penerima organ transplan Penderita kelainan katup jantung yang akan menjalani tindakan invasif Tindakan bedah untuk mencegah infeksi akibat perlukaannya

Langkah-langkah

Proses Keputusan Pemilihan & Pemakaian Antibiotik

Penegakan diagnosa infeksi Kemungkinan kuman penyebabnya Apakah antibiotik benar-benar diperlukan Alternatif Jika diperlukan antibiotika : Spektrum antikuman Pola sensitifitas Sifat farmakokinetik Ada tidaknya kontra indikasi Ada tidaknya interaksi yang merugikan Penentuan dosis, cara pemberian, lama pemberian, evaluasi dan efek samping Keadaan fisik pasien seperti : adanya kelainan ginjal, fungsi hati, usia, berat badan dan sebagainya Harga

10 Important Questions To Ask Before Selecting an Antibiotic

1. 2.

Adapted from: Richard E. Reese, Principles of Antibiotics Use, 2000

Is an antibiotic indicated? Have appropriate specimens been obtained, examined and cultured? 3. What organism are most likely? 4. If several antibiotics are available, which is the best? 5. Is an antibiotic combination appropriate? 6. What are the important host factors? 7. What is the best route of administration? 8. What is the appropriate dose? 9. Will initial therapy require modification after culture date are returned? 10. What is the optimal duration of treatment, and is development of resistance during prolonged therapy likely to occur?

Site of action of some common antibacterial drugs

RNA synthesis Rifampicin DNA synthesis Quinolones

Folic acid antagonist Sulphonamides Trimethoprim

All of the above action will exhibit bactericidal effects, except the action on protein synthesis and folic acid antagonist resulting bacteriostatic effects For some indications combination therapy is indicated. However the bacteriostatic or bactericidal agents should not be mixed (Chris J.V. Boxtel, Drug Benefits and Risks, 2001)

Cell membran Polymyxins

Cell wall Penicillins Cephalosporins Vancomycin Teicoplanin

Protein synthesis Erythromycin Aminoglycosides Tetracycline Linezolid

Adapted from: Roger Finch, Antimicrobial Therapy, Medical Progress. Feb,2011

An important strategy for a successful AM therapy in severe infections

Select a regiment that maximize the rate and extent of bacterial killing Rationale : Suboptimal therapy maybe life threatening in the treatment of severe infections Slow bacterial killing will likely give chance for the responsible pathogen to develop resistance.

Adapted from: Kim & Nicolau, 2002

The concept of Pharmacokinetic/Pharmacodynamics (PK/PD) has been increasingly applied to optimize the clinical use of antimicrobial agents and delay the growth of resistant pathogens to promote rational use of drug

Manfaat parameter PK/PD bagi penggunaan antibiotika dalam klinik

Penentuan dosis yang lebih benar dan tepat Peramalan efikasi kliniknya Peramalan kemungkinan terjadinya resistensi kuman selama pengobatan Berguna bagi penentuan formulasi pengembangan antibiotika yang baru

concentration

Relationship between the pharmacokinetic profile of an antibiotic and the minimum inhibitory concentration against a hypothetical target organism
Minimum inhibitory concentration (MIC)
Time above minimum inhibitory concentration Peak (Cmax) Area under the curve > minimum inhibitory concentration (AUC)

A
B C D

A B

time
Adapted from:

Roger Finch, Antimicrobial Therapy, Medical Progress. Feb,2011

Pattern of concentrationdependent killing

concentration

Cmax

Eg. Aminoglycosides Fluoroquinolones

MIC

time

Pattern of timedependent killing

concentration

Eg. Betalactam Macrolides Clindamycin

MIC

time

Antibiotics : The more you use it, the faster you lose it

Antibiotic resistance are increasing and actually around the world Development of bacterial resistance to antibiotics is much faster than research and development of new antibiotics (Robert A. Weinstein, The Epidemiology of Antibiotic Resistance, June 2007) But doctors can improve their prescribing practices and thats a big effort in hospitals

Outcomes Measure

Relative Risk of Worse Outcomes for Infections with Resistant Compared with Susceptible Bacteria
1.0 1.7 1.0 1.7 1.3 5.0

Hospital length of stay (LOS) Hospital charges Mortality

Clinical Impact of Resistance

Adapted from: Cosgrove : Clin Infect Dis. 2006, 42:S82-89

US antibioticresistance are responsible for

$35 billion+ in societal cost

$20 billion+ in excess healthcare cost

$8 billion+ additional hospital days

Adapted from: Centers for Disease Control and Prevention Bulletin. Nov 17, 2010)

Resistant Gram bacteria terminology

Resistant Gram-positive bacteria terminology PRSP MDRSP MRSA VRSA VISA (GISA) VRE (GRE) Penicillin resistant streptococcus pneumoniae Multidrug resistant streptococcus pneumoniae Methicillin resistant staphylococcus aureus Vancomycin resistant staphylococcus aureus Vancomycin (Glycopeptide) intermediate staphylococcus aureus Vancomycin (Glycopeptide) resistant enterococcus

Resistant Gram-negative bacteria terminology ESBL-producing enterobacteriaceae

MRPA (MDR-PA) MRAB (MDR-AB)

Extended spectrum beta-lactamases producing Enterobacteriaceae e.g. Escherichia coli, Klebsiella pneumoniae
Multidrug resistant pseudomonas aeruginosa Multidrug resistant acinetobacter baumannii Pan-resistant Pseudomonas aeruginosa/Acinetobacter baumannii

IDSA (Infections Diseases Society of America) supports :

The 10x20 Initiative : Pursuing global commitments to develop 10 new antibacterial drugs by 2020
Adapted from : Clinical Infection Diseases 2010:50:1081-1083

Alih Terapi Antibiotika

Mengalihkan pengobatan IV secepatnya ke oral pada pengobatan infeksi tertentu di rumah sakit

Keuntungan :
Memperpendek masa rawat Mengurangi kejadian nosokomial melalui jarum infus Mengurangi komplikasi thromboflebitis Menurunkan biaya pengobatan Switch Therapy Obat IV dan oral berlainan namun potensi antibakterinya sama Sequential Therapy Obat IV dan oral adalah sama dan obat oral diserap dengan baik mis: ofloksasin Stepdown Therapy Obat IV dialihkan ke oral yang potensinya lebih lemah. Mis : ceftriaxone IV ke cefuroxime aksetil oral

Macam-macam alih terapi :

Alih Terapi (IV-PO Switch) dapat dilakukan setelah :

Perbaikan klinis atau parameter infeksi lain setelah 2-3 hari Tidak adanya indikasi lanjutan diberi antibiotika IV Tidak ada gangguan pada saluran cerna Bebas demam lebih kurang dua hari Adanya perubahan leukosit, hitung jenis dan protein fase akut ke arah normal

IV antimicrobials are indicated in :

Meningitis Intracranial abscess Infective endocarditis Mediastinitis Severe infections during chemotherapy-related neutropenia Inadequately drained abscess and empyema Severe soft tissue infections S. aureus or P. aeruginosa bacteremia

Antibiotic Stewardship Program

Optimal selection, dosage and duration of antimicrobial treatment that

Results in the best clinical outcome for the treatment or prevention of infection With minimal toxicity to patient and With minimal impact on subsequent resistance

Involves
Prescribing antimicrobial therapy only when it is beneficial to the patient Targeting therapy to the desired pathogens Using the appropriate drug, dose and duration

A strategy to enhance patient safety by :

Minimizing exposure to drugs Performing dose adjustments Reducing redundant therapy Targeting therapy to the likely pathogens

ASP in Hospital Authority

Objectives
Control the emergence and spread of antibiotic resistance Optimize selection and use of antibiotics Cost containment

Multidisciplinary, programmatic, prospective, interventional approach to optimizing the use of antimicrobial agents The multidisciplinary team typically includes
Clinical microbiologists Infectious diseases specialists Clinical pharmacists Infection control practitioners

Recommended antibiotics for most common pathogens isolates from cultures

MRSA : vancomycin, teicoplanin, linezolid and daptomycin ESBL : Carbapenems, piperacillintazobactum, cefaperozone-sulbactum, amoxycillin-clavulinate Enterococcus : linezolid, teicoplanin, vancomycin Acinetobacter : colistin in combinations with rifampin and imipenem, rifampin and ampicilin-sulbactam or colistin and rifampin only VRE : Linezolid, daptomycin, high dose ampicillin with aminoglycoside

Adapted from: A.Bhagwati, Guidelines for antibiotic usage in common situations, Dec.2010)

Take Home Messages

Resistensi terhadap antibiotika tetap berkembang pesat Penggunaan antibiotika harus sesuai indikasi dengan segala aspeknya Upaya penghematan biaya penderita di RS (terapi alih) perlu diterapkan ATP Program penting untuk dikembangkan agar menunjang keberhasilan pengobatan dengan antibiotika yang rasional

Thanks for your attention!