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ANTIBIOTICS SMART USE (ASU) การใช้ยาต้านจุลชีพอย่างชาญฉลาด. Pornpan Koomanachai Division of Infectious diseases and Tropical Medicine Department of Medicine, Faculty of Medicine Siriraj Hospital. ASU. A major threat to public health ปัญหาหลักทางสาธารณสุข. ASU.

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slide1

ANTIBIOTICS SMART USE (ASU)

การใช้ยาต้านจุลชีพอย่างชาญฉลาด

PornpanKoomanachai

Division of Infectious diseases and Tropical Medicine

Department of Medicine, Faculty of Medicine Siriraj Hospital

.

slide2
ASU

A major threat to public health

ปัญหาหลักทางสาธารณสุข

slide3
ASU

Costelloe C et al.BMJ 2010;340:c2096

  • Antibiotics
    • Commonly used in ambulatory care facility

(ใช้บ่อย)

    • Antibiotics can be purchased without prescriptions (ซื้อเองได้)
  • 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
slide4
ASU

Asawapokee N et al. J Infect Dis Antimicrob Agents 1984; 3: 141-5

Treebupachatsakul P et al. J Med Assoc Thai 2006;89(8):1178-86

  • URI and acute diarrhea: common self-limiting

(การติดเชื้อทางเดินหายใจส่วนต้นและท้องร่วง

เฉียบพลัน)

  • 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
slide5
ASU
  • In healthy individuals with acute diarrhea
    • almost always self-limited; หายได้เอง!!!!
  • Standard guidelines การใช้ยาต้านจุลชีพต้องมีข้อบ่งชี้สำคัญ คือ
    • 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
slide6
ASU

สำนักงานคณะกรรมการอาหารและยา

สถาบันวิจัยระบบสาธารณสุข

องค์การอนามัยโลก

slide7
ASU

1. เป้าหมาย คือ ลดการใช้ยาปฏิชีวนะอย่างพร่ำเพรื่อใน 3 โรคที่พบบ่อย

- โรคติดเชื้อทางเดินหายใจส่วนบน

- โรคท้องร่วงเฉียบพลัน

- แผลเลือดออก

2. ASU เป็นโครงการที่หวังผลให้เกิดการเปลี่ยนแปลงทางพฤติกรรม

3. ASU เหมาะกับสถานพยาบาลที่การสั่งใช้ยาปฏิชีวนะมากเกินจำเป็นมีสาเหตุมาจาก

- ความรู้หรือความเชื่อที่คาดเคลื่อนของบุคลากรทาง การแพทย์

- แรงกดดันหรือความคาดหวังของผู้ป่วย

4. ASU ตั้งอยู่บนแนวคิดที่ว่าการเปลี่ยนพฤติกรรมเริ่มจากความรู้ แต่ความรู้อย่างเดียวไม่เพียงพอในการเปลี่ยนพฤติกรรม

principle of antibiotic used
PRINCIPLE OF ANTIBIOTIC USED

Common Inappropriate Use of Antibiotics

  • CHOOSING ANTIBIOTIC THERAPY BASED SOLELY ON

SPECTRUM เลือกใช้ยาโดยดูแต่ความสามารถในการครอบคลุมเชื้อ

  • PROLONGED USE OF IV ANTIBIOTICS ใช้ยาฉีดเป็นเวลานาน
  • USE OF COMBINATION THERAPY TO PREVENT ATB

RESISTANCE ใช้ยามากกว่า 1 ขนานเพราะเชื่อว่าจะป้องกันการดื้อยา

  • OVERRELIANCE ON MICROBIOLOGY RESULTS เลือกใช้ยาตามผลเพาะเชื้อเพียงอย่างเดียว
  • USE OF ATB FOR PERSISTENT FEVERS ใช้ยาต้านจุลชีพเพราะไข้ไม่ลดลง
  • INADEQUATE SURGICAL THERAPY AND LACK OF NON-ATB

THERAPY OF INFECTION ขาดการรักษาร่วมอื่นๆที่สำคัญ

  • PROLONGED ATB THERAPY OR PROPHYLAXIS ใช้ยานานเกินความจำเป็น
choosing atb based solely on spectrum
CHOOSING ATB BASED SOLELY ON SPECTRUM

Antibiotic tissue penetration

ระดับยาในตำแหน่งที่มีการติดเชื้อ

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

choosing atb based solely on spectrum1
CHOOSING ATB BASED SOLELY ON SPECTRUM

Antibiotic tissue penetration

ระดับยาในตำแหน่งที่มีการติดเชื้อ

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
choosing atb based solely on spectrum2
CHOOSING ATB BASED SOLELY ON SPECTRUM

Antibiotic tissue penetration

ระดับยาในตำแหน่งที่มีการติดเชื้อ

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

  • 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 antimicrobial

efficacy

choosing atb based solely on spectrum3
CHOOSING ATB BASED SOLELY ON SPECTRUM

Antibiotic tissue penetration

ระดับยาในตำแหน่งที่มีการติดเชื้อ

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

  • Poor Tissue Concentration of ATB
    • Tigecycline Urinary tract (Lung, Blood)
    • Daptomycin Lung
    • 1st- and 2nd-gen ceph. blood-brain barrier
    • Macrolides blood-brain barrier
choosing atb based solely on spectrum4
CHOOSING ATB BASED SOLELY ON SPECTRUM

Bectericidal vs Bacteriostatic therapy

การออกฤทธิ์ของยาในการยับยั้งการติดเชื้อ

  • Bactericidal agents cause

death and disruption of the

bacteria

    • Disruption of cell wall
    • ß-lactams
    • cell membrane
    • daptomycin
    • Bacterial DNA
    • fluoroquinolones
  • Bacteriostatic agents

inhibit bacterial replication

without killing the organis

    • inhibiting protein synthesis
    • sulfonamides
    • tetracyclines
    • macrolides

*Bactericidal agents are in the serious infections to achieve rapid

cure such as endocarditis and meningitis

prolonged use of iv antibiotics
PROLONGED USE OF IV ANTIBIOTICS

IV-to-PO switch therapy

เปลี่ยนยาฉีดเป็นยารับประทาน

  • Barrier for intravenous-to-oral (IV-to-PO)

นิสัยไม่ดีเก่าๆแก้ยาก!!!!

“ 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
Why! Oral antibiotic therapy

Advantages (ข้อดี)

Disadvantages (ข้อด้อย)

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)

  • 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

Cunha BA. Antibiotic essentials. 5th edition. 2006

Cunha BA. Drugs Today 2001;37:311–9

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

when oral antibiotic therapy
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
Requirements of an oral ATB

Antibiotic Factors

ปัจจัยด้านยาต้านจุลชีพ

Host Factors

ปัจจัยด้านผู้ป่วย

patient able to sufficiently absorb an oral antibiotic

avoid in patients with impaired gastrointestinal absorption

  • high degree of activity against presumed/known pathogens
  • high bioavailability
  • low resistance potential
  • well tolerated with a good safety profile
duke university medical centre criteria
Duke University Medical Centre Criteria

ตัวอย่าง

  • Absent of infectious indications requiring parenteral ATB
  • 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: 249

J Infect 1998; 37(suppl 1):3-9

duke university medical centre criteria1
Duke 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: 249

J Infect 1998; 37(suppl 1):3-9

what are types of iv to oral switch
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

ศาสตราจารย์แพทย์หญิงนลินี อัศวโภคี

bioavailability of oral antibiotics
Bioavailability of oral antibiotics

Keflex

Meiact

Cefspan

Cedax

Zinacef

Vantin

use of combination therapy
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
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
Combination vs monotherapy

PRO

ข้อมูลสนับสนุน

CON

ข้อมูลคัดค้าน

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

  • Synergistic effect – in vitro
  • Good outcome in severely ill

(Septic shock, neutropenia)

  • Higher rate of

microbiological cure

CID 2011;53 (Suppl 2):S33

ICAAC 2011, Chicago & IDSA 2011 Sa n Francisco, USA

combination therapy to prevent atb resistance
COMBINATION THERAPY TO PREVENT ATB RESISTANCE

Antibiotic combinations that

prevent resistance

  • Anti-pseudomonal penicillin + aminoglycoside
  • Rifampin + other TB drugs

(INH, ethambutol, pyrazinamide)

(3) 5-flucytosine + amphotericin B

(4) Anti-retroviral drugs in HIV/AIDS therapy

slide27

COMBINATION THERAPY TO PREVENT ATB RESISTANCE

Commonly used antibiotic combinations

that do not prevent resistance

ยาที่นิยมใช้ให้หลายขนาน

แต่ในความเป็นจริงไม่ได้ป้องกันเชื้อดื้อยา

  • TMP-SMX
  • Ceftazidime in combination with any other ATB
  • Ciprofloxacin in combination with any other

ATB

(4) Imipenem in combination with any other ATB

(5) Most other ATB combinations

overreliance on microbiology results
OVERRELIANCE 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

overreliance on microbiology results1
OVERRELIANCE 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

use of antibiotics for persistent fever
USE OF ANTIBIOTICS FOR PERSISTENT FEVER

The most common error in the management of

persistent fevers

  • Changing/adding additional antibiotics instead

of determining the cause ปรับยาไม่มีการวินิจฉัย

  • 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
use of antibiotics for persistent fever1
USE 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
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 of

immunosuppressive agents

    • CMV disease in organ transplant recipients or patients with

rheumatologic disorders

  • Probiotics

Lancet Infect Dis 2004;4(3):139-143

N Engl J Med 2004;351(17):1741-1751

N Engl J Med 1990;323(21):1444-1450

Anaerobe 2009;15(6):274-280

prolonged atb therapy or prophylaxis
PROLONGED 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
prolonged atb therapy or prophylaxis1
PROLONGED ATB THERAPY OR 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
prolonged atb therapy or prophylaxis2
PROLONGED ATB THERAPY OR 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):752-760

JAMA. 2003;290(19):2588-2598

prolonged atb therapy or prophylaxis3
PROLONGED ATB THERAPY OR 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

prolonged atb therapy or prophylaxis4
PROLONGED ATB THERAPY OR 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
Case Study

48-year-old man

  • Fever 8 wks
  • Left cervical lymphadenopathy 8 wks
  • Nausea, vomiting, and hiccup 8 wks
  • Weight loss 5kg/6wks
  • Chronic hepatitis C infection 3 yrs
  • Hepatomegaly with jaundice
  • Anemia
differential diagnosis
Differential diagnosis
  • Lymphoma
  • TB/Nontuberculous mycobacterium (NTM)
  • Infectious mononucleosis (EBV)
  • Solid tumor: CA nasopharynx, CAesophagus,

Hepatoma

  • *HIV (Opportunistic infection or lymphoma)
  • Histoplasmosis
  • CMV
  • Cat scratch disease
  • Hepatitis C
case study1
Case Study

58-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
case study2
Case Study
  • 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.

  • 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
case study3
Case Study
  • 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.

  • Increasing adverse effect; renal toxicity without
  • any benefit
messages
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
slide44

Thank you

Pornpan Koomanachai, MD