항생제 사용의 원칙2009.4.20

건국대학교 충주병원 감염내과 기세윤

2008 년 건대병원 항생제 삭감률

62.1

49.4

34.7

14.7 12.8 10.6

4.1

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

Antibiotics 1st & 2nd Cefa Aminoglycoside QuinoloneAntibiotics Cefa 1st&2nd C 3rd C AMG Imipenem Quinolone

%

Start with the question“Is an antibiotic needed in this patient?”

Avoid antibiotics in patients only- with Fever- with only URI

Sx ≥ 1 week, should not be started immediately- Get sufficient information including cultures

Urgent “probable” infectionsMeningitisFebrile neutropenia

Definite evidence of localized infectionsPneumoniaCellulitisUTI

Start with the question“Is an antibiotic needed in this patient?”

Three players in Antimicrobial therapy

Antimicrobial therapy

Antibiotics Host

Microorganism

Microbiologic factor

Causative pathogen - Guessing Empirical therapy - Identifying Targeted therapyAntimicrobial susceptibility

Inoculum ( 접종수 ) Growth phase Virulence factors (toxin, enzymes, metabolites)

Guessing

Using Bacteriologic Statistics Site of infection Age Severity of disease Epidemiological factors Previous culture results Antimicrobial susceptibility

pattern of the community ““Best-guess” antibiotic Best-guess” antibiotic

therapytherapy

Site of infection Common pathogen

PneumoniaS. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae

Skin and soft tissue S.aureus, S.pyogenes

Intraabdominal infection Enterobacteriacae, Anaerobes

Meningitis

<55yr S.pneumoniae, N.meningitidis

>55yrs or alcoholics

GNB, L.monocytogenes, S.pneumoniae

Febrile neutropenia P.aeruginosa, GNB

UTI E.coli – TMP/SMX R 70%

Identifying

Gram stainingCulture & sensitivity testing BEFORE starting/changing antibiotics

SerologyPCRAg detection

Host factors

Site of infection Drug allergy, Genetic factor Renal, Hepatic function Age – children, elderly Pregnancy, Breast feeding Underlying disease – DM, Hematologic

malignancy, Transplantation recipient Immunity – Immunosuppressant, Immune-

deficiency

Site of infection

Determines class, dose, route of antibiotics Blood –tissue barrier CNS - 3rd cepha, Penicillin O 1st, 2nd cepha, AMG X Prostate – Quinolone O b-lactam, AMG X Foreign bodies, Vegetation, bone, devitalized tissue Low penetration of antibiotics Biofilms – impair phagocytosis,↓ antibiotics penetration Abscess Pus, anaerobic, low PH condition → AMG X ** Drainage is important!

Antimicrobial spectrum

Efficacy

PK, PD

Safety and toxicity

Cost-effectiveness

Drug interactions

Antimicrobial factors

Classification of antibiotics Class 　 Mechanism of action

Beta-lactams Cell wall synthesis

Penicillin

　 Cephalosporin 　　 Beta-lactamase inhibitor 　　 Carbapenem 　　 Monobactam 　Fluoroquinolone 　 DNA synthesisAminoglycoside 　 Protein synthesisGlycopeptide 　 Cell wall synthesisMacrolides 　 Protein synthesisLincosamide 　 Protein synthesisTetracycline 　 Protein synthesisMetronidazole 　 Nucleic acid synthesisSulfonamides 　 Cell metabolism Oxazolidinone Protein synthesis

Polymyxin Cell membrane

Penicillin

G (+) G (-)Anaerobe

s

Natural Pn Penicillin G+ (non b-lactamase producing)

Neisseria +

Penicillinase resistant Pn

Nafcillin Staphylococcus - -

AminoPn Ampicillin/Amoxicillin

+ (non b-lactamase producing)

++ +

Anti-Pseudomonal Pn

Piperacillin+ (non b-lactamase producing)

+++ +

CephalosporinGeneration Examples G(+) S.pneumoniae G(-)

1stCefazolin Cefazedone ( 세파제돈 )Ceftezole( 세로스린 )

+++ +++ +

2ndCefuroxime ( 세프록심 )Cefotiam ( 세라도란 , 폰티암 )

++ ++ ++

Cepha-mycin

Cefoxitin ( 세폭시틴 )Cefotetan ( 세포테탄 )Cefmetazole ( 셉타신 ) Cefbuperazone ( 토미포란 )

++ ++ ++

3rdCefotaxime( 세포탁심 )Ceftriaxone ( 트리악손 )Ceftizoxime ( 에포세린 )

+ +++ +++

　 Cefoperazone ( 페라탐 ) Ceftazidime + +

+++Pseudomona

s

4th Cefepime +++ ++++++

Pseudomonas

Anaerobes

B-lactam + B-lactamase combination

G(+) G(-)Anaerob

es

Ampicillin/Sulbactam ( 루카신 ) ++ + +

Amoxicillin/Clavulanic acid ( 크라목신 ) ++ + +

Piperacillin/Tazobactam ( 타조페란 ) ++++

Pseudomonas

+

Cefoperazone/Sulbactam ( 페라탐 ) +++

Pseudomonas

+

Carbapenem

IMI/CL MER ERT

G(+) ++ + +

G(-)

Enterobacteriaceae + ++ ++

P. aeruginosa + ++

Anaerobes ++ ++ ++

Quinolones

Generation

Fluoroquinolones Antibacterial activity

1st Nalidixic acid, oxolinic acid, cinoxacin Enterobacteriaceae

2nd Ciprofloxacin, pefloxacin, Norfloxacin, Ofloxacin, Lomefloxacin

Mainly G(-), Limited G(+)

3rd Levofloxacin, sparfloxacin, temafloxacin

Both G(+) and G(-)

4th Moxifloxacin, gatifloxacin, gemifloxacin

Both G(+) and G(-) + Anaerobes

Other AntibioticsG(+) G(-) Note

Aminoglycoside GentamicinTobramicinAmikacinIsepamicinMicronomicin

MSSA (+)Should not

be used alone

+

Glycopeptide VancomycinTeicoplanin + - MRSA

Macrolides ClarithromycinErythromycin + Atypical

pathogen

Lincosamide Clindamycin + - Anaerobes

Tetracycline Doxycycline Rickettsia

Metronidazole 　 - - Anaerobes

Sulfonamides TMP-SMX + +

Oxazolidinone Linezolid + - VRE

Polymyxin Colistin - +

Broad-spectrum, 3rd line antibiotics

Piperacillin/Tazobactam ( 타조페란 ) Imipenem, Meropenem Vancomycin, Teicoplanin Moxifloxacin ( 아벨록스 ) Linezolid, Colistin

Do not waste them! More colonization with resistant organisms

Superinfection with resistant organismHigher morbidity and mortality

Multidrug resistant organisms (So called Superbacteria)

MDRO Current TOC New options

MRSAVancomycinTeicoplaninLinezolid

DaptomycinTigecyclineTelavancin..Ceftobiprole

VRE LinezolidDaptomycinTigecyclineTelavancin..

ESBL + GNBImipenemMeropenem …

MDR Pseudo/Acineto Colistin …

Combination therapy? Indication

Mixed infectionIntra-abdominal infection, pelvic infection

Initial therapyFebrile neutropenic patientSeverely septic patient with presumed infection

Prevent emergence of resistanceAnti-Tb tx, H.pylori tx

Synergism Entercococci: penicillin +AGS. aureus: nafcillin + GMP. aeruginosa : piperacillin + AG

Disadvantages of combination

AntagonismPneumococcal meningitis

Mortality: penicillin 21% vs PCN+tetracycline 79%Enterobacter, Serratia, Pseudomonas

Beta lactam + beta lactam: beta lactamase induction Higher costs Toxicity Superinfection ( 균교대 ) Emergence of resistant organism

Pharmacokinetics/Pharmacodynamics(PK/PD)

Pharmacodynamics

[C] @infection

site

Pathogen

MIC

DrugPharmacokinetics

Outcome Absorption Distribution Metabolism Excretion

Time-dependent killing Concentration-dependent killing PAE

Cure / failure Microbiologic

• quantitative

Symptoms• rate of response

• Dx-free interval

GI tract (po) Vessel, Muscle (parenteral) Absorption

Distribution

Biotransformation

Excretion

Kidney Hepatobiliary

Antibiotic

Route of administration

Severity of infection Site of infection

Oral bioavailability Vancomycin, AMG, amphotericin B PO≠IV Linezolid PO=IV Quinolone PO ≈IV

Function of GI tract Severely ill patient Antacid, antihistamine:↓FQ absorption

poor fair good excellent 0% 40% 70% >90%

Penicillin VAmpicillinCefuroximeCefixime( 슈프락스 )Cefpodoxime( 바난 )AzithromycinClarithromycinNorfloxacin

AmoxicillinAmox/clavTetracyclineCiprofloxacinMetronidazole

Cefadroxil, Cefaclor( 유로세프 , 세파클러 )Cefprozil ( 세프질 )DoxycyclineOfloxacinLevofloxacinClindamycin TMP/SMZ

VancomycinAminoglycosides

GI absorption rate of antibiotics

Antibiotics Ass.drug Results

Fluoroquinolones

Antacids, Sucralfate, Didanosine (ddI), Ferrous sulfate, Zinc

concentration d/t chelation

TetracyclinesAntacids, Bismuth, subsalicylate, Didanosine (ddI), Ferrous sulfate

concentration d/t chelation

Clindamycin Kaolin-pectin absorption

Drug interactions inhibiting GI absorption

Appropriate dose

Check textbook!! Higher dose Toxicity

Exception - CNS infection d/t blood-brain barrier - Decreased host immunity: neutropenic fever

Lower dose Resistance

Drug level monitoring- Drugs: low therapeutic/toxic ratio (AMG, Vanco)- Indications: renal dysfunction, elderly

Pharmacodynamic parameters of antibiotics

Concentration dependent

Time dependent

Streamline, sequence and monitor the antimicrobial therapy

0 1 2 3 4 5 6 7 d 2 wk 4wk

1st Empirical or Deferred 2nd Re-evaluation or

Definitive, or Continuous

3rd Step-down or Discontinue

Stages of Antibiotic Therapy

1st Empirical or Deferred Stage (1st 24 hours)

1. Best-guess antibiotic therapy 2. Consider Host factors3. Consider Antimicrobial factors

4. Hold antibiotic therapy for about 24 hours for patients with less possibility of bacterial infection and immune-competent state

2nd Re-evaluation, Definitive, or Continuous Stage (3rd-5th days)

1. Evaluate the efficacy

- Consider delayed response among compromised hosts

2. Definitive therapy

- Identify the cultured microorganisms and choose susceptible antibiotics

3. Continuous therapy

- No growth of microorganisms and good clinical response

4. Re-evaluate

- If no clinical response, re-evaluate the clinical situation

Modification with culture data is essential!!

Check culture results (Reported within 3-5 days)

Switch antibiotics according to culture resultsPossible narrow spectrum antibiotics

MSSA: vancomycin→nafcillin or 1st cefa S E.coli : 2nd cefa, ampicillin, TMP-SMX

Less toxicity GNB: AMG →beta lactam (ampicillin, cefa)Cheap

AMG: Gentamicin (\870) vs Isepamicin (\2,754)

3rd Step-down or Discontinuous Stage (5th –14th days)

1. Stop - No clinical and microbiological signs of infection an

d minimun duration satisfied

2. Step down - Oral switch if criteria fullfilled

3. Adjust - Superinfection, infection w resistant pathogen, opp

ortunistic infections

Monitoring response

Clinical assessment: most important - Fever: Sensitive indicator Defeverescence within 3-5 d usually - Local Sx.: cough, sputum, diarrhea, abd. pain, headache - Physical Fx.: rales, discharge, erythema, pain, swelling

Laboratory parameters - Routine Lab : WBC count, shift to left, CRP, ESR - Microbiology : f/u cultures (blood, urine)

Imaging studies - X-ray, Ultrasonography, CT scan, MRI

Suggested Duration of Antibiotic TherapySite Clinical Dx. Duration of Tx. Bacteremia Bacteremia with removable focus 10-14Bone Osteomyelitis, adult; acute 42

adult; chronic Until ESR normal

Endocardium Infective endocarditis, native valve

Viridans strep. 14 or 28

Enterococci 28 or 42

Staph. aureus 14(Rt. Only) or 28 GI Shigellosis/traveller’s diarrhea 3

Typhoid fever FQ (10) or ceftriaxone (5)

Kidney Cystitis 3

Pyelonephritis 14Lung Pneumonia, pneumococcal Until afebrile 3-5 d (min. 5d)

Lung abscess 28-42 Meninges H. influenzae, N. meningitidis 7

S. pneumoniae 10-14

Listeria, Gr. B strep., coliforms 14-21 Sinuses Acute sinusitis 10-14

Optimal duration

Adequate period, not unnecessarily prolongedTo avoid colonization by resistant organismsPneumonia: X-ray improves slowly

Recommended duration: textbookType of infection, pathogens, host immunityFollow recent data for shorter treatment

Acute cystitis: 7d → 3dScrub typhus: 7d → 3d

Surgical prophylaxis

If the patient is improving and organisms resistant to current antibiotics is isolated on F/U cultures

Ignore it!

Reasons for treatment failure Delay in diagnosis or therapy Wrong or incomplete diagnosis

No infectionNonbacterial infection

Inadequate concentration of antibiotic at the site of infectionImproper doseDecreased absorption from food or drug interactionIncreased elimination of agentPoor delivery (eg, vascular disease)

Other factors at the site of infectionCollection requiring drainageNecrotic tissueForeign body

Decreased activity at the siteChemotactic factor (pH and others)Antibiotic antagonism

Other host factorsImpaired immune defenses

Errors in antimicrobial susceptibility testing Development of resistance to antimicrobial agents Superinfection

Take home message

Perform cultures Confirm correct dosesCombination is not needed most of the

timeCheck culture resultsHold as soon as possible

Antibiotics

Desirable effectsUndesirable effect

Toxicity

Resistance

Anti-anxiety drug???

합리적합리적 , , 효과적 항생제 요법효과적 항생제 요법

항생제 선택 - 효과 및 안전성 - 용량 , 용법 , - PK, PD

세균감염 ?원인균 ?항생제 내성 ?

효과 판정 부작용 관찰투여기간