항생제 사용의 원칙 2009.4.20 건국대학교 충주병원 감염내과 기세윤. 2008 년...
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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?”
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
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
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
합리적합리적 , , 효과적 항생제 요법효과적 항생제 요법
항생제 선택 - 효과 및 안전성 - 용량 , 용법 , - PK, PD
세균감염 ?원인균 ?항생제 내성 ?
효과 판정 부작용 관찰투여기간