항생제사용원칙 성균관대학교의과대학삼성서울병원감염내과 백경란
내용 감염질환개요 항생제개요 항생제사용원칙 2
감염질환의성립 숙주 ( 사람 ) 저항력면역기전 병원성병독력침입경로침입량 병원체 ( 미생물 ) 환경 생물학적인자계절적인자지리적인자사회적인자 항생제 3
미생물과의접촉 오염 (contamination) : 일시적 정착, 집락화 (colonization) 단순히증식하면서서식 정상세균총 (normal flora) : 비병원성균주 병원성균의집락화 감염 (infection) : 미생물의침입과증식 불현감염 현증감염 Þ 치료의대상 4
감염질환의치료 보조적대증요법 해열제 진통제 항생제투여 항생제 : 병원체의증식억제또는살균 반드시필요한경우에투여 : 해열제가아님 5
항생제의오남용 의료비용의증가 항생제부작용의위험 항생제내성유도 Þ 치료적항생제선택에어려움 6
항생제처방평가 주체 건강보험심사평가원 보건복지가족부 대상 상기도감염 폐렴 수술시예방적항균제 항생제바르게쓰기 7
용어 항생제 (Antibiotics) Waksman 최초로기술 (1942) from antibiosis against symbiosis 공생 세균의성장을억제하거나살균하는제제 살아있는미생물이생산 ( 세균이나진균등 ) 항균제 (Antimicrobial agents) 광범위용어 : 천연물질, 합성제제, 반합성제제 8
항균제의개발 9
항균제 근대의학에서가장중요한발전 영향 감염질환의효과적인치료 high-tech medicine의발전 항암치료, 면역치료, 수술, 장기이식 모든감염질환은 소멸될것이다 10
항균제사용의문제점 항균제에대한과신 항균제의오. 남용 항균제내성 11
주요항균제내성의역사 Penicillin Vancomycin Methicillin, oxacillin Cephalosporin 1942 58 60 1970 1980 1945 61 67 1986 1996 2002 2008 VRE 페니실린내성폐렴구균 MRSA 페니실린내성포도구균 VRSA VISA 12
현재상황 내성균발생과전파 Speed up 새로운항생제개발 Slow down Back to the pre-antibiotic era? 13
앞으로의방향 새로운항생제개발 항생제의신중한사용 적절성과임상효과 내성발생예방 내성전파예방 14
항균제의적절한사용 항균제 작용기전, 항균력 약동학 / 약력학 부작용 원인균 감수성 / 내성양상 환자 감염부위 기저질환 적정용량 적정기간 15
작용기전에따른항생제분류 세포벽합성 b-lactams Glycopeptides DNA 합성 Quinolones Folic acid FABA FOLIC ACID 합성 Sulfonamides Trimethoprim 세포막합성 Polymyxijn 단백합성 Aminoglycosides Macrolides Fusidic acid 16
세균의분류 호기성세균 그람양성균 : 포도구균, 폐렴구균 그람음성균 장내세균 : 대장균 비발효세균 : 녹농균 혐기성세균 17
베타락탐계항균제 Penicillins b-lactamase Cephalosporins Monobactams Carbapenems 18
페니실린계 Natural PC : PC-G (procain, benzathine), PC-V Penicillase-resistant PC Methicillin, Oxacillin, Nafcillin Extended-spectrum PC Aminopenicillin: Ampicillin, Amoxicillin Carboxy-PC: Carbenicillin, Ticarcillin Ureido-PC: Piperacillin PC + b-lactamase inhibitor Ampicillin + Sulbactam (Unasyn) Amoxicillin + Clavulanate (Augmentin) Ticarcillin + Clavulanate (Claventin) Piperacillin + Tazobactam (Tazocin) 19
MRSA, 장구균에대한항균력없음 세팔로스포린계 1 세대 cefazolin, cephalothin, cephradine, cephalexin, cefadroxil 2 세대 cefamandole, cefotetan, cefoxitin, cefuroxime, 3 세대 cefonicid, cefmetazole, cefaclor, loracarbef, cefprozil cefotaxime, ceftriaxone, ceftizoxime, ceftibuten, moxalactam, cefpodoxime cefoperazone, cefpiramide, ceftazidime 4 세대 : cefepime 20
Ceftobiprole 항균범위 그람양성균 MRSA vancomycin-intermediate and -resistant S. aureus Ampicillin 감수성장구균 (E. faecalis, E. faecium) Vancomycin 내성 E. faecalis 그람음성균, but not ESBL Pseudomonas aeruginosa No activity against metallo-β -lactamase-producers no useful activity against ampi/vanco R E. faecium 21
Carbapenem Imipenem/cilastatin (1985) Meropenem (1996) Ertapenem (2004) Panipenem (Japan) Doripenem (Dorivax) Carbapenems 22
Carbapenem 의항균력 광범위항균력 호기성세균 : GPC, GNB - Except - MRSA VRE Staphylococci, pneumococci, streptococci Enterococci Haemophilus, Moraxella, Enterobacteriaceae Pseudomonas, Acinetobacter 혐기성세균 Bacteroides 항산균 (Mycobacterium) M. fortuitum, M. chelonae, M. tuberculosis Carbapenems 23
광범위항균력 Principle of antibiotic therapy Pros Antibiotics with a narrow spectrum of activity should be selected to minimize the selective pressure Initial therapy in severe infections Polymicrobial infections Carbapenems 24
Carbapenem 1 차치료에실패한경우 Beta-lactams : cephalosporin, tazocin 1 차약제에내성인균이증명된경우 ESBL(+) Pseudomonas, Acinetobacter 중증감염에초기경험적치료 균동정후다른약제로조절 Carbapenem 내성균 25
Vancomycin, Teicoplanin 내성균감염 MRSA Ampicillin-resistant Enterococcus 균동정후다른약제로조절 경험적치료 1. 신경외과 수술후중추신경계감염 2. Prosthesis 관련골수염또는관절염 3. 인공호흡기관련폐렴 4. ( 안구내염 ) 5. CAPD 복막염 6. ( 지역사회에서발생한급성세균성뇌수막염 ) 7. 면역저하환자에서중증감염 ( 악성종양, 장기이식, 면역억제제사용 ) 예방적투여 원칙적으로불인정 개심수술 - 일부인정 26
Teicoplanin 의장점 Advantages of Teicoplanin over Vancomycin è less frequent dosing: once daily IM injection less nephrotoxicity & ototoxicity 27
Linezolid 최초의 oxazolidinone계열의항생제 세균의단백합성을저해 항균력 MRSA, VRE 적응증 MRSA 폐렴 (Vanco 치료실패의경우 ) VRE 감염증 28
Quinolone Core structure Generations I IIa IIb IIIa IIIb Fluoroquinolones Flumequine Ciprofloxacin, Ofloxacin, Levofloxacin Grepafloxacin, Sparfloxacin Moxifloxacin, Gatifloxacin Sitafloxacin, Clinafloxacin Naphthyridone Nalidixic acid Enoxacin Tosufloxacin Trovafloxacin Gemifloxacin 29
Quinolone 비교적광범위항균력 그람양성균 : S.aureus, Streptococcus, ( 폐렴구균 levo, moxi, gati, gemi) 그람음성균 : E.coli, Klebsiella Pseudomonas (cipro >>) 혐기성균 (moxifloxacin, gatifloxacin) 항산균 단점 : 획득내성, 약물상호작용 30
Clinical use of FQ Cipro : UTI, prostatitis GI and abdominal infection Acute bacterial diarrhea or travelers diarrhea, salmonellosis, typhoid fever, shigellosis Levo, moxi, gemi, gati : Community-acquired respiratory tract infections Nosocomial pneumonia: can be used as initial agent in some Pseudomonas infection Bone & joint infections: chronic OM Mycobacterial infections : 1 차약제내성 31
Tigecycline Tetracycline 유도체 Tetracycline 내성균주에항균력 그람양성균 : MRSA, VRE 그람음성균 Pseudomonas 에항균력없음 혐기성세균 현재복강내감염, 피부연조직감염에승인 다제내성 Acinetobacter 감염증? 32
새로운항진균제 New generation of an existing class Voriconazole Posaconazole Agents of a new class with different mechanism of action Echinocandin : cell wall-active agents Caspofungin Micafungin Anidulafungin (phase 3) 33
Echinocandin Inhibitors of the fungal cell wall β-(1,3)-d-glucan synthase enzyme Distinct site of action Specific target to fungus Less toxic to human No cross resistance with polyenes, azoles Fungicidal activity with osmotic lysis Candida Caspofungin The first echinocandin approved Micafungin 34
Caspofungin 항진균범위 Fungicidal activity against Candida spp. : C albicans, C tropicalis, and C glabrata Even fluconazole resistant Candida Fungistatic against Aspergillus spp. Limited activity against C neoformans because little or no β-(1,3)-d-glucan synthase Susceptibility testing Not standardized Correlation between the results of susceptibility tests and the clinical outcome is unclear 35
Voriconazole The second generation triazole Derivative of fluconazole Addition of a-methyl group Fungicidal against Aspergillus and moulds Expanded spectrum of activity Inhibit cytochrome P450 dependent 14 a- lanosterol demethylase ( ergosterol synthesis inhibition) Affinity : yeast << moulds fungistatic fungicidal 36
Voriconazole 항진균범위 Candida spp. Including fluconazole resistant C krusei, C glabrata Cryptococcus, Trichosporon, Saccharomyces Aspergillus spp. Including AmB resistant A terreus Fusarium, Scedosporium, Blastomyces, Histoplasma No activity against zygomycetes 37
임상적응증 Voriconazole Caspofungin Invasive aspergillosis Primary therapy? Refractory or intolerant to other antifungal therapies Oral therapy to complete course Candidiasis Fluconazole resistant candidiasis Refractory or intolerant to other antifungal therapies 38
Caspofungin/voriconazole 보험인정 Amphotericin B 치료에실패 총용량 500mg 이상투여 7일이상 Cr 상승등의심한부작용 2.5 이상 기저수치의 2 배이상상승 39
항생제투여용량, 간격조정 약동학 농도, 배설, 분포 약력학 MIC 기준 농도의존성살균력 시간의존성살균력 40
Pharmacodynamics: Bactericidal activity Conc. MIC Dose-dependent killing INJECTION Time 41
Pharmacodynamics: Bactericidal activity Conc. MIC Time-dependent killing INJECTION Time 42
Pharmacodynamics: Bactericidal activity Dependent Antibiotics Targets Parameters Dose AGs, Quinolones Metronidazole Maximal Conc. Peak/MIC AUC/MIC Time PCs, Cephs, Carbapenems Clindamycin Macrolides Maximal Duration T>MIC 43
항생제사용원칙 Q1. 항생제투여가필요한가? Avoid antibiotics in patients only with viral infection, e.g. URI with Fever Sx. ³ 1 week, should not be started immediately 44
Judicious use of available antibiotics To use or Not to use 45
Q2. 배양검체채취 그람염색 그람양성균 in cluster: Staphylococci 그람양성균 in chain: streptococci. enterococci 항생제투여전배양검사시행 When available, initial antibiotic can be altered Follow-up cultures are less reliable Anaerobic cultures (eg, abscess) 46
Q3. 가장가능성높은원인균은? 경험적항균제 환자 감염질환및감염부위 감염질환의중증도 가능성있는원인균 국내자료 내성양상 Pneumonia : pneumococcus UTI : E.coli 47
감염과화학요법 2005;37:133-137 2005;37:138-143 폐렴구균의항균제감수성 항균제감수성 (%) MIC 50 MIC 90 Amoxicillin 32.5 4 16 Amox/clavulanate 32.5 4/2 16/8 Cefaclor 8.5 64 128 Cefdinir 12 8 16 Cefixime 12 16 16 Cefprozil 16.2 8 16 Cefuroxime 15.4 8 16 Cefcapene - 0.125 1 Cefditoren 97.4 0.5 1 Ceftriaxone 100 0.5 1 Clarithromycin Telithromycin 14.5 - > 32 > 32 0.5 Levofloxacin 98.3 1 1 48
Q4. 어느항생제를투여할것인가? 선택적치료제 : 교과서, 가이드라인 약물부작용, 알러지 Cost of antimicrobial agents Cost of antibiotic itself Only part of total cost of antibiotic administration Frequency of administration Personnel time and materials Number of antibiotics Monitoring of blood level Management for toxicity 병실입원료 효과가유사하다면저렴한항생제 Amphotericin vs. Caspofungin / voriconazole 49
Q5. 병합투여를할것인가? 적응증 중증감염 복합균감염 단점 길항작용 : 단일제제투여에비해치료효과감소 고비용 부작용발생위험증가 내성세균의선택 50
Q6. 고려해야할환자측요소 연령 임산부 기저질환 면역저하자 신부전증 간부전증 51
Q7. 적절한투여경로는? 비경구 vs. 경구투여 중증도 >> 감염부위 : 뇌수막염, 심내막염 >> 위장관흡수율 : 제제별특성 위장관기능 경구요법 Vancomycin IV ¹ PO 경증또는중간중증도의감염질환 외래치료 감염질환의비경구치료후호전을보이기시작하면치료완료는경구로바꾸어서치료할수있다. Linezolid, voriconazole : 높은위장관흡수율 52
Q8. 적정용량투여 교과서및가이드라인에서확인 충분한치료효과, 낮은부작용발생율 내성유도를최소화 혈중약물농도 monitoring Vancomycin, aminoglycoside 적응증 : 고령자, 신기능저하자 허가사항보다높은용량투여할수있다. 53
항생제용량 CNS infection such as Meningitis * Blood-brain barrier (ceftriaxone 2g bid, vancomycin 30 mg/kg bid) Neutropenic fever * Decreased host immune (cefepime 2g bid, ceftazidime 2g tid) 54
Q9. 배양결과에따른항생제조절 * 임상적효과와배양결과 De-escalation 좁은항균범위 MSSA : vancomycin nafcillin, cefazolin More effective killing, more focused spectrum Carbapenem cephalosporin 적은부작용 GNB : AG beta lactam (ampicillin, cepha) 저렴한약가 Carbapenem cephalosporin, piperacillin/tazobactam 55
If the patient is improving and an organisms resistant to the antibiotics is isolated on F/U sputum or wound cultures, Ignore it! 56
내성발생 Broad spectrum antibiotics Þ Þ Þ More colonization with resistant organisms Superinfection with resistant organisms Higher morbidity and mortality Use the new broad-spectrum agents carefully Þ Minimize development of bacterial resistance 57
Q10. 치료기간은언제까지? 적정치료기간 불필요하게장기간치료않도록 내성균의선택을예방하기위해 폐렴 : X ray 상호전은서서히나타남 교과서, 가이드라인참조 치료기간이점점짧아지고있다. 심내막염 : 2 wk for some selected cases 급성방광염 : 7 d 3 d 쯔쯔가무시병 : 7 d 3 d 따라서최신자료참조필요적정기간 58
수술시예방적항생제 목적 수술창상감염예방 부적절한사용 ( 제제, 시기, 기간 ) 약제부작용 수술창상감염증가 내성균감염발생위험 59
수술시예방적항생제 수술의분류 청결창상 : NS, OS, heart, thyroid, breast, hernia 청결-오염창상 : GS 오염창상 : bowel perforation 불결창상 : infected 치료적항생제 60
Clean wound ( 청결창상 ) 일부예방적항생제투여가효과가있다는연구 갑상선수술, 인공관절치환술 병합투여불필요 심평원에서불인정사례증가추세 병합투여규제 61
예방적항생제의종류 피부상재균에작용하는제제 1 세대 cephalosporin 대장수술 : 장내상재균, 혐기성균 Cefotetan, cefoxitin 3 세대 cephalosporin 사용규제 62
예방적항생제투여기간 수술시작 30 분전, 1 회투여로충분 수술이길어지는경우추가투여가능 24 시간을넘기지않도록한다. 63
Prolonged prophylaxis in coronary artery bypass graft surgery Harbarth et al. Circulation 2000;101:2916 Cefazolin or vancomycin or ceftriaxone No difference in SSI < 48 h vs. > 48 h Not decreased risk of SSI (OR 1.2; CI, 0.8-1.6) Increased risk of acquired resistance (OR,1.6; CI, 1.1-2.6) 48 시간초과사용규제추가적경구용항균제처방제한 64
항균제의적절한사용 항균제 작용기전, 항균력 약동학 / 약력학 부작용 원인균 감수성 / 내성양상 환자 감염부위 기저질환 적정용량 적정기간 65
올바른항균제사용을위한방안 교육 ( 의료진전체, 임상과별 ) 항균제사용지침 제한항균제시스템 항균제사용실태모니터링 병원약전 (drug formulary) 통제 항균제감수성검사결과의제한적보고 항균제처방전산프로그램활용 66