ANTIBIOTICS SMART USE (ASU) การใช้ยาต้านจุลชีพอย่างชาญฉลาด

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดล

.

Pornpan Koomanachai Division of Infectious diseases and Tropical MedicineDepartment of Medicine, Faculty of Medicine Siriraj

Hospital

Pornpan Koomanachai Division of Infectious diseases and Tropical MedicineDepartment of Medicine, Faculty of Medicine Siriraj

Hospital


ASU

A major threat to public healthปั�ญหาหล�กทางสาธาร์ณส�ข


ASUAntibiotics

Commonly used in ambulatory care facility (ใช้�บ่�อย) Antibiotics can be purchased without

prescriptions (ซื้�อเองได้�)

A systematic review and meta-analysis Antibiotic prescribing in primary care Prescribing an antibiotic in primary care

for a respiratory or urinary infection develop bacterial resistance to that antibiotic Costelloe C et al.BMJ 2010;340:c2096


ASU

URI and acute diarrhea: common self-limiting (การติ�ด้เช้�อทางเด้�นหายใจส่�วนติ�นและท�องร�วง เฉี�ยบ่พล!น)

The prevalence of group A streptococci (GAS) in adults with sore throat attending Siriraj Hospital 7.9% to 11.4%

No compelling data on antibiotic treatment of patients with URI other than GAS are beneficial

Asawapokee N et al. J Infect Dis Antimicrob Agents 1984; 3: 141-5Treebupachatsakul P et al. J Med Assoc Thai 2006;89(8):1178-86


ASU

In healthy individuals with acute diarrhea almost always self-limited; หายได!เอง!!!!

Standard guidelines การใช้�ยาติ�านจ"ลช้�พติ�องมี�ข้�อบ่�งช้��ส่%าคั!ญ คัอ empiric antibiotic therapy is recommended

only for invasive or inflammatory diarrhea especially in special hosts with

immunocompromised conditions non-inflammatory diarrhea with moderate or

severe dehydration such as cholera


ASU

ส$านั�กงานัคณะกร์ร์มการ์อาหาร์และยาสถาบ�นัวิ�จั�ยร์ะบบสาธาร์ณส�ข

องค การ์อนัาม�ยโลก


ASU

1. เป้)าหมีาย คัอ ลด้การใช้�ยาป้ฏิ�ช้�วนะอย�างพร%+าเพร+อใน 3 โรคัท�+พบ่บ่�อย

- โรคัติ�ด้เช้�อทางเด้�นหายใจส่�วนบ่น - โรคัท�องร�วงเฉี�ยบ่พล!น - แผลเลอด้ออก

2. ASU เป้.นโคัรงการท�+หว!งผลให�เก�ด้การเป้ล�+ยนแป้ลงทางพฤติ�กรรมี 3. ASU เหมีาะก!บ่ส่ถานพยาบ่าลท�+การส่!+งใช้�ยาป้ฏิ�ช้�วนะมีากเก�นจ%าเป้.นมี�ส่าเหติ"มีาจาก

- คัวามีร1 �หรอคัวามีเช้+อท�+คัาด้เคัล+อนข้องบ่"คัลากรทาง การแพทย2

- แรงกด้ด้!นหรอคัวามีคัาด้หว!งข้องผ1�ป้3วย4. ASU ติ!�งอย1�บ่นแนวคั�ด้ท�+ว�าการเป้ล�+ยนพฤติ�กรรมีเร�+มีจากคัวามีร1 � แติ�คัวามีร1 �อย�างเด้�ยวไมี�เพ�ยงพอในการเป้ล�+ยนพฤติ�กรรมี


PRINCIPLE OF ANTIBIOTIC USED

Common Inappropriate Use of AntibioticsCHOOSING ANTIBIOTIC THERAPY BASED SOLELY ON

SPECTRUM เลอกใช้�ยาโด้ยด้1แติ�คัวามีส่ามีารถในการคัรอบ่คัล"มีเช้�อPROLONGED USE OF IV ANTIBIOTICS ใช้�ยาฉี�ด้เป้.นเวลานาน USE OF COMBINATION THERAPY TO PREVENT ATB

RESISTANCE ใช้�ยามีากกว�า 1 ข้นานเพราะเช้+อว�าจะป้)องก!นการด้�อยาOVERRELIANCE ON MICROBIOLOGY RESULTS เลอกใช้�ยาติามีผลเพาะเช้�อเพ�ยงอย�างเด้�ยวUSE OF ATB FOR PERSISTENT FEVERS ใช้�ยาติ�านจ"ลช้�พเพราะไข้�ไมี�ลด้ลงINADEQUATE SURGICAL THERAPY AND LACK OF NON-ATB

THERAPY OF INFECTION ข้าด้การร!กษาร�วมีอ+นๆท�+ส่%าคั!ญPROLONGED ATB THERAPY OR PROPHYLAXIS ใช้�ยานานเก�นคัวามีจ%าเป้.น

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลCHOOSING ATB BASED SOLELY ON

SPECTRUM

Antibiotic tissue penetrationร์ะด�บยาในัต$าแหนั*งท+,ม+การ์ต�ดเช-.อ

ATB effective in-vitro, unable to reach the site of infection

Urinary tract infections; same pathogens but! drugs for catheter-associated bacteriuria and cystitis

differ from those used for pyelonephritis, prostatitis, or epididymitis

Fluoroqyuinolones: high concentration in the prostate**moxifloxacin; not achieve significant urinary concentration


SPECTRUM


ATB effective;in-vitro, unable to reach the site of infection

Chronic infections - decrease vascular permeability chronic pyelonephritis, chronic prostatitis, chronic

osteomyelitis

Implanted foreign materials biofilm- slime/glycocalyx on plastic/metal surfaces


SPECTRUM



Special barrier or abscesses ocular, fluid, CSF, abscess cavity, prostate, bone

aminoglycosides; less active in the low-oxygen, low-pH, and high-protein environment of abscesses

** drainage of abscesses to enhance antimicrobialefficacy


SPECTRUM



Poor Tissue Concentration of ATB

Tigecycline Urinary tract (Lung, Blood) Daptomycin Lung 1st- and 2nd-gen ceph. blood-brain barrier Macrolides blood-brain barrier


SPECTRUM

Bactericidal agents cause death and disruption of the bacteria Disruption of cell wallo ß-lactams cell membrane o daptomycin Bacterial DNA o fluoroquinolones

Bacteriostatic agents inhibit bacterial replication without killing the organis inhibiting protein

synthesiso sulfonamideso tetracyclineso macrolides

Bectericidal vs Bacteriostatic therapyการ์ออกฤทธ�0ของยาในัการ์ย�บย�.งการ์ต�ดเช-.อ

*Bactericidal agents are in the serious infections to achieve rapid cure such as endocarditis and meningitis

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลPROLONGED USE OF IV

ANTIBIOTICS

IV-to-PO switch therapyเปัล+,ยนัยาฉี+ดเปั2นัยาร์�บปัร์ะทานั

Barrier for intravenous-to-oral (IV-to-PO) นั�ส�ยไม*ด+เก*าๆแก!ยาก!!!! “ Physicians are creatures of habit, and old habits die hard”… Burke A. Cunha, MD (Infectious Disease Division,

Winthrop-University Hospital, Mineola, NY 11501, USA)

IV therapy: first used for serious systemic infections Many infections susceptible to IV ATB IV therapy: the preferred mode of ATB

administration


Why! Oral antibiotic therapy

Advantages (ข!อด+)

Lower ATB acquisition cost No IV ATB administration

costs Rapid gastrointestinal

absorption (<1 h) even in critically ill patients

Eliminates IV-line infections Decreased length of

hospital stay Earlier discharge

Disadvantages (ข!อด!อย)

Should not be used in those with impaired gastrointestinal absorption

Patient in shock, begin therapy intravenously

Increased ecological hazard(oral agent with poor bioavailability potentiate colonization)

Cunha BA. Antibiotic essentials. 5th edition. 2006 Cunha BA. Drugs Today 2001;37:311–9

Quintiliani R, Nightingale CH. Infect Dis Clin Practice 1994;3(Suppl):161–7

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลCost-effectiveness! IV-to-Oral Switch

therapy

The study of cost-effectiveness

Cost saving/reduction

Tuscon, AZ, USA, 2007by Patanwala AE.

from $ 11479, to $ 8923 per a treatment course

Switzerland, 2003von Gunten V.

44 to 92 Euros per a treatment course

Buffalo, NY, USA, 2002by Paladino JA.

from $6,145 to $5,265 per a treatment group

Hartford, CT, USA, 1993 by Nightingale CH.

$150,000 - $250,000 per year

Vancouver, 1994by Jewesson P.

$C 21,5 00 per year

Netherland, 1992 by Janknegt

NG 67,160 per patient per day


When! Oral antibiotic therapy

Oral absorption in the critically ill

- Oral ATBwith good/excellent bioavailability rapidly/well absorbed achieve blood/target tissue levels **except septic shock

- Per oral per nasogastric tube or per percutaneous enteroscopic gastroscopy tube


Requirements of an oral ATB

Antibiotic Factorsปั�จัจั�ยด!านัยาต!านัจั�ลช+พ

high degree of activity against presumed/known pathogens

high bioavailability low resistance

potential well tolerated with a

good safety profile

Host Factorsปั�จัจั�ยด!านัผู้5!ปั6วิย

patient able to sufficiently absorb an oral antibiotic

avoid in patients with impaired gastrointestinal absorption

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลDuke University Medical Centre

Criteria

ต�วิอย*างAbsent of infectious indications requiring parenteral ATB• febrile neutropenia• significantly immunocompromised• meningitis• osteomyelitis• endocarditis• septic shock • disseminated viral infections such as HSV

• febrile neutropenia• significantly immunocompromised• meningitis• osteomyelitis• endocarditis• septic shock • disseminated viral infections such as HSV

* Modified from Lelekis and Gould. J Hosp Infect 2001; 48: 249J Infect 1998; 37(suppl 1):3-9

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลDuke University Medical Centre

Criteria Absent of infectious indications requiring parenteral ATB

Infection is not presently serious or life-threatening

Improved of signs or symptoms of infection

Afebrile or has consistent improvement in fever > 24 hrs

WBC count is normalizing

Normal gastrointestinal absorption of drugs and the patient is able to receive enteral therapy

* Modified from Lelekis and Gould. J Hosp Infect 2001; 48: 249J Infect 1998; 37(suppl 1):3-9


What are types of IV-to-oral switch?

Stream-lining: converting from broad-spectrum ATB to single agent with narrow spectrum

Sequential: converting IV to oral agents with same chemical

Switch: converting IV to oral agents with identical potency

Step-down: converting IV to oral agents with reduced potency ศาสตร์าจัาร์ย แพทย หญ�งนัล�นั+ อ�ศวิโภค+


Bioavailability of oral antibiotics

> 95%

90-95% 80-89% < 80%

Cephalexin Clindamycin Amoxicillin Amoxycillin/Clavulanic

acid

Cotrimoxazole Doxycycline Ampicillin/Sulbactam

Clarithromycin

Levofloxacin Ofloxacin Ciprofloxacin Dicloxacillin

Linezolid Tetracycline Cefditoren pivoxil

Metronidazole Cefixime

Ceftibuten

Cefuroxime axetil

Cefpodoxime proxitil

KeflexKeflex

MeiactMeiact

CefspanCefspan

VantinVantin

Zinacef

Zinacef

CedaxCedax


USE OF COMBINATION THERAPY?

Monotherapy; preferred over combination therapy -> reduces the risk of; drug interactions medication errors missed doses and side effects usually less expensive than combination therapy

Combination Therapy drug synergy extended spectrum


Combination Therapy: Synergy

β-lactams and aminoglycosides exhibits

synergism for treatment of endocarditis caused by; Enterococcus spp. A viridans group streptococci Staphylococcus aureus

Penicllin and clindamycin: clinical synergism for treatment of S. pyogenes infection


Combination vs monotherapy

PROข!อม5ลสนั�บสนั�นั

Synergistic effect – in vitro

Good outcome in severely ill (Septic shock, neutropenia)

Higher rate of microbiological cure

CONข!อม5ลค�ดค!านั

Higher rates of resistance isolates

Higher rates of side effects

Lack of the power to showed the consistent of good outcome

No top level of grading evidence

CID 2011;53 (Suppl 2):S33ICAAC 2011, Chicago & IDSA 2011 Sa n Francisco, USA


COMBINATION THERAPY TO PREVENT ATB RESISTANCE

Antibiotic combinations that prevent resistance

(1) Anti-pseudomonal penicillin + aminoglycoside

(2) Rifampin + other TB drugs (INH, ethambutol,

pyrazinamide) (3) 5-flucytosine + amphotericin B(4) Anti-retroviral drugs in HIV/AIDS therapy


Commonly used antibiotic combinations that do not prevent resistance

ยาท+,นั�ยมใช!ให!หลายขนัานัแต*ในัควิามเปั2นัจัร์�งไม*ได!ปั8องก�นัเช-.อด-.อยา

(1) TMP-SMX (2) Ceftazidime in combination with any other

ATB(3) Ciprofloxacin in combination with any other

ATB(4) Imipenem in combination with any other ATB(5) Most other ATB combinations

COMBINATION THERAPY TO PREVENT ATB RESISTANCE

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลOVERRELIANCE ON MICROBIOLOGY

RESULTS

In vitro data do not differentiate between colonizers and pathogens determine whether the organism is a pathogen or a

colonizer colonization should not be treated

In vitro data do not necessarily translate into in vivo efficacy "sensitive" or "resistant" to a given antibiotic in-vitro do not necessarily reflect in-vivo activity

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลOVERRELIANCE ON MICROBIOLOGY

RESULTS

In vitro susceptibility testing is dependent on the microbe, methodology, and ATB concentration; assumes the isolate was recovered from blood, and is being exposed to serum concentrations Usually higher ATB concentrations than in serum:

bladder, urine Lower ATB concentrations than in serum: CSF, ocular In vitro data may be misleading for non-bloodstream infections

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลUSE OF ANTIBIOTICS FOR PERSISTENT

FEVER

The most common error in the management of persistent fevers Changing/adding additional antibiotics

instead of determining the cause ปัร์�บยาไม*ม+การ์วิ�นั�จัฉี�ย

More important to reassess the patient Causes of prolonged fevers include

Non-infectious medical disorders (e.g., SLE) Drug fever In-vitro susceptibility but inactive in-vivo

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลUSE OF ANTIBIOTICS FOR PERSISTENT

FEVER

Inadequate spectrum Inadequate ATB blood

and tissue levels

Undrained abscess, Foreign body-related

infection Special barrier CSF Organ hypoperfusion

diminished blood supply - chronic osteomyelitis in diabetics)

ATB inactivation, ATB antagonism)

Fungal superinfection Treating colonization ATB-unresponsive

infectious diseases; viral infections

Undiagnosed causes of leukocytosis

Low-grade fevers should not be treated with prolonged courses of ATB


NON-ATB THERAPY OF INFECTION

Operative drainage or débridement Get rid of the high organism burden (abscesses)

Corticosteroid: conjunction with ATB therapy Bacterial meningitis Tuberculous meningitis Pneumocystis pneumonia in AIDS

Temporary discontinuation or dose reduction ofimmunosuppressive agents CMV disease in organ transplant recipients or patients

with rheumatologic disorders

Probiotics Lancet Infect Dis -20044 3 139143; ( ):

N Engl J Med -20043511717411751

N Engl J Med 1990;323(21):1444-1450Anaerobe -200915 6 274280; ( ):

คณะแพทยศาสตร์ ศ�ร์�ร์าชพยาบาล มหาวิ�ทยาล�ยมห�ดลPROLONGED ATB THERAPY OR

PROPHYLAXIS

Duration of ATB therapy Prolonged courses of ATB therapy

Potential for adverse reactions Problems with adherence Selection of ATB-resistant organisms High cost


PROPHYLAXIS

Potential for adverse reactions Direct

Allergy Toxicity Drug-drug interaction Therapeutic failure

Indirect Effects on commensal flora

• Human Clostridium difficile infection• Animal Increased chance of infection with

drug-resistant pathogens

Effects on environmental flora


PROPHYLAXIS

Duration of ATB therapy Examples of optimal duration, shorter but

effective course Uncomplicated UTI in women 3 days Community-acquired pneumonia 5 days Ventilator-associated pneumonia 8 days

** not sufficient for the treatment of infections due

to P. aeruginosa or in immunocompromised patients Endocarditis, osteomyelitis, 4-6 weeks

and intra-abdominal abscesses Cochrane Database Syst Rev 2005;(2):CD004682

Clin Infect Dis. 2003;37(6):752-760JAMA. 2003;290(19):2588-2598


PROPHYLAXIS

Duration of ATB prophylaxis

Presurgical ATB prophylaxis To reduce the incidence of postoperative

surgical site infections

The ATB should cover the most likely organisms and be present in the tissues

At the initial incision

Clin Infect Dis. 2004;38(12):1706-1715


PROPHYLAXIS

Duration of ATB prophylaxis

Presurgical ATB prophylaxis Adequate serum concentrations during the

procedure A single dose of a cephalosporin (such as

cefazolin) within 1 hour before the initial incision

Avoiding unnecessary broad-spectrum ATB Duration; should not exceed 24 hours

Clin Infect Dis. 2004;38(12):1706-1715


Case Study

48-year-old manFever 8 wksLeft cervical lymphadenopathy 8

wksNausea, vomiting, and hiccup 8 wksWeight loss 5kg/6wksChronic hepatitis C infection 3 yrsHepatomegaly with jaundiceAnemia


Differential diagnosisLymphomaTB/Nontuberculous mycobacterium

(NTM) Infectious mononucleosis (EBV)Solid tumor: CA nasopharynx,

CAesophagus,

Hepatoma*HIV (Opportunistic infection or lymphoma)HistoplasmosisCMVCat scratch diseaseHepatitis C


Case Study58-year-old man Necessary Investigations were performed

Blood smear H/C for bacteria, mycobacteria, fungus LN biopsy BM aspiration and biopsy CT; Nasopharyx, thorax, abdomen

He was treated with ceftriaxone 2g iv, OD for 3 days.

Fever was still high and LFT (hepatocellula rinjury) was worsening with anemia, thrombocytopenia, leucopenia.

The ATB was changed to meropenem at day-3 of ceftriaxone.

• No appropriate provisional diagnosis• Use ATB to treat prolonged fever• Changed ATB without reassessment the patient

• No appropriate provisional diagnosis• Use ATB to treat prolonged fever• Changed ATB without reassessment the patient


Bone marrow and LN: Lymphoma with hemophagocytis Treatment - IVIg, Dexamethasone IV -> clinical improved Chemotherapy

The patient developed febrile neutropenia. Septic work up was performed and meropenem was

prescribed for 5 days and the fever was decreasing while neutrophil was increasing from 150 to 820.

Sputum culture grew A. baumannii on day-5 of meropenem then colistin was prescribed, continued meropenem.

Case Study

• Use ATB based on culture result to treat colonization• Changed ATB without reassessment the patient• ATB as a risk of adverse effect; renal toxicity without any benefit• ATB cost, IV administration cost but no “cost effectiveness

• Use ATB based on culture result to treat colonization• Changed ATB without reassessment the patient• ATB as a risk of adverse effect; renal toxicity without any benefit• ATB cost, IV administration cost but no “cost effectiveness


The patient still has low grade fever after 7 days of colistin, neutrophil was increasing from 150 to 1,020. Cr rising from 1.2 -> 3.2, sputum C/S grew A. baumannii but resist to colistin. Clinical is similar to previously but this time, no ATB was prescribed.

Case Study

• Increasing adverse effect; renal toxicity without any benefit

• Increasing adverse effect; renal toxicity without any benefit


Messages

What is the damage of inappropriate ATB?

Morbidity & mortality Adverse effects High cost-

ineffectivesness Emergence of

resistant

How to get appropriate ATB?

An accurate diagnosis The need for ATB, which ATB

and timing of ATB Rx Using the narrowest

spectrum

and shortest duration of Rx Switching to oral agents

ASAP Dosing regimens of different

agents Host characteristics Non-ATB interventions


Pornpan Koomanachai, MD

Documents

ANTIBIOTICS SMART USE (ASU) การใช้ยาต้านจุลชีพอย่างชาญฉลาด