대한내과학회지 : 제 81 권제 6 호 2011 특집 (Special Review) - 흔한감염질환에서의항생제내성및최신치료 지역사회획득폐렴에서의항생제내성및최신치료 경북대학교의학전문대학원내과학교실 김신우 Antibiotic Resistance and Treatment Update of Community-Acquired Pneumonia Shin-Woo Kim Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea The emergence of penicillin-resistant S. pneumoniae has issued in the management of community-acquired pneumonia (CAP). However, the clinical outcome did not match with penicillin resistance. Thus, recent (Jan/2008) change of penicillin breakpoints for nonmeningeal strain was done and this made prevalence of penicillin resistance under 5% worldwide. Macrolide resistance of S. pneumoniae in Korea is prevalent (70-80%). Thus, the Korean CAP guideline did not include macrolide monotherapy as empiric therapy. Fluoroquinolone resistance of pneumococcus is very low, however, concerning of the increase of resistance is present. Some new antibiotics for the multidrug resistant S. pneumoniae should be reserved for the future. Macrolide resistance of Mycoplasma pneumoniae is reported in various regions in the world, however, data of the clinical significance is rare. Increased β- lactamase production of Haemophilus influenzae urges us to use β-lactam/β-lactamase or 3rd generation cephalosporin if Haemophilus is pathogen. Pneumococcal vaccine usage is an effective way to prevent invasive diseases by S. pneumoniae (including resistant pathogen). The rate of pneumococcal vaccination in Korea is very low (0.8% in adult). Strategies to control resistance that include effective antimicrobial treatment, vaccination, infection control, appropriate policies and regulations, antibiotic stewardship and education of appropriate antibiotic use, are greatly in need. (Korean J Med 2011;81:690-698) Keywords: Pneumonia; Bacterial drug resistance; Antibiotic treatment 서론지역사회획득폐렴은항생제치료에도불구하고사망률이 12-14% 에이르며감염성질환중가장흔한사망원인중하나이다 [1]. 지역사회획득폐렴의원인균은보고에따라차이가있지만, 가장흔한원인균은국내에서도국외와마찬가지로 Streptococcus pneumoniae이다 (20-60%) [1-3]. 그다음으 로는 Mycoplasma pneumoniae, Haemophilus influenzae 및 Chlamydophila pneumoniae 등이다 [4]. 항생제내성문제는 S. pneumoniae와 H. influenzae 와같은정형 (typical) 폐렴의원인체의주된문제이지만, 최근비정형 (atypical) 폐렴의대표적원인체인 M. pneumoniae의 macrolide 내성도증가한다고보고되고있다 [5-7]. 여기서는지역사회획득폐렴의대표적세균성원인체들 Correspondence to Shin-Woo Kim, M.D. Department of Internal Medicine, Kyungpook National University Hospital, 130 Dongdeok-ro, Jung-gu, Daegu 700-721, Korea Tel: +82-53-420-6525, Fax: +82-53-424-5542, E-mail: ksw2kms@knu.ac.kr - 690 -
- Shin-Woo Kim. Resistance and treatment of pneumonia - 의항생제내성문제가지역사회폐렴의치료에어떤영향을미치고있는지를살펴보고치료적측면에서어떤선택이가장적절하며또한새로운치료로는어떤것이기대되는지알아보고자한다. 본론 Streptococcus pneumoniae의항생제내성 S. pneumoniae 의 penicillin 내성현황과그임상적의의 S. pneumoniae는지역사회획득폐렴, 수막염, 부비동염, 중이염등의흔한원인균으로임상적으로매우중요한균이다. S. pneumoniae의 β-lactam 항생제에대한내성기전은 penicillin binding protein (PBP) 의변성에의한다 [2]. 특히 PBP1a, 2x 및 2b의변형은 β-lactam계항생제의최소억제농도 (minimal inhibitory concentration, MIC) 를올리는결과를가져온다 [2]. 1967년기관지확장증에서처음 penicillin 내성균주가확인된이후내성률은꾸준하게증가하고있다 [4]. 우리나라는 1995년 S. pneumoniae의 penicillin에대한내성률이 70-77% (2008년 1월이전감수성기준적용 ) 로보고되어 [8] 큰사회적영향을미쳤다. 1990년대이후 penicillin에내성을나타내는균주가급속히증가하고있었다 [9]. 이는전세계적인현상이었으며 [10] 국내 S. pneumoniae의 penicillin 내성률이 50-80% 로지속적으로보고되면서내성률이가장높은나라가운데하나로알려졌다 [11,12]. 국내의약분업의시작시 항생제내성률이높다 는등의사안이중요하게이야기되었다. 그러나당시보고된항생제내성률조사에포함된검체는지역사회폐렴환자만을대상으로연구된것은아니며, 신체여러부위에서얻어검사실로보내져배양검사가의뢰된다양한임상검체 ( 침습성균주와보균균주를포함 ) 를대상으로 한결과였다. 질환의원인이아닌집락 (colonization) 균주까지포함된경우가많았다. 더욱이침습성균주보다집락균의내성이일반적으로더크다 [13]. 또한혈액이나뇌척수액에서분리된경우내성균의비율이낮으나호흡기검체는내성균비율이더높다 [14]. 또한호흡기검체중에도객담보다는상기도에서얻은검체가훨씬내성균비율이높다는점을이자료를해석할때고려하여야한다. 당시내성기준에의하면임상적치료에서실패의위험이커져가는상황이지만외국의여러임상연구에서 penicillin 내성여부는임상경과와큰연관성이없으며, 감염부위에따라 penicillin의치료효과에차이가있는것으로보고되었다 [15-17]. 국내에서도유사한결과가보고되었다 [18-20]. Penicillin 비감수성균주에의한수막염인경우에는 penicillin으로치료하기는어려우나, 폐렴인경우는다른항균제에비해서 penicillin계의치료효과가떨어지지않는다고생각된다 [18, 19,21]. 이러한연구결과와항생제약력학 / 약동학적지식의발전으로인하여 CLSI (Clinical and Laboratory Standards Institute) 는 2008년 1월 M100-S18을통해 S. pneumoniae에대한 penicillin breakpoints를변경하였다. 기존에는임상증상이나 penicillin 투약경로에관계없이최소억제농도가 0.06 μg/ml 이하이면감수성, 0.12-1 μg/ml 이면중간내성, 그리고 2 μg/ml 이상이면내성이던것을수막염여부및 penicillin 투약경로에따라최소억제농도의 breakpoints를변경하였다 (Table 1). 이새로운기준을적용한경우감수성이달라진다 (92.6% 감수성, 7.1% 중등도내성, 0.3% 에서내성 ; 전세계적으로모은 8,882균주에대해조사 ) [22]. 국내에서도이와유사한연구에서기존의기준을사용한경우총 156균주의 S. pneumoniae 중 penicillin 감수성은 66균주 (42.3%), 중간내성은 66균주 (42.3%), 내성은 24균주 (15.4%) 인반면, 개정이후기준을적 Table 1. Revised penicillin breakpoints for Streptococcus pneumoniae (Jan 2008)-Clinical and Laboratory Standards Institute Susceptibility category MIC (μg/ml) Standards Susceptible Intermediate Resistant Before 0.06 0.12-1 2 After Jan 2008 Meningitis, intravenous penicillin 0.06 - a 0.12 Non-meningitis, intravenous penicillin 2 4 8 Nonmeningitis, oral penicillin 0.06 0.12-2 2 a No intermediate category for meningitis under new penicillin breakpoints. - 691 -
- 대한내과학회지 : 제 81 권제 6 호통권제 616 호 2011 - 용하면 penicillin 감수성이 137균주 (87.8%), 중간내성이 15균주 (9.6%), 내성이 4균주 (2.6%) 로됨을보고하였다 [23]. 기준의변경으로말미암아 penicillin 계열의항생제에대한내성은전세계적으로 5% 미만이된상황이다. Penicillin계항생제가치료효과에있어다른계열에비해뒤지지않는다는많은보고에도불구하고현재많은임상의들은지역사회획득폐렴의경험적치료에 ampicillin/sulbactam 또는 amoxicillin/calvulanate보다 ceftriaxone 또는 cefotaxime 을주로선택하고있는실정이다 (unpublished data). 현재국내가이드라인과미국의가이드라인에서도 ampicillin/sulbactam 또는 amoxicillin/calvulanate을외래와일반병실로입원을하는환자들에게사용할수있는것으로기록하고있다 (Table 2) [1,4]. Ampicillin/sulbactam 또는 amoxicillin/calvulanate 을 ceftriaxone 또는 cefotaxime 과비교하는잘수행된임상적비교연구는상업적관심의대상이아니어서잘이루어지지는않고있으며향후이주제에대한좋은연구결과가나오기를기대한다. 또한임상의들의실제적인경험이필요하다. Penicillin 최소억제농도의정도에따라다른 β-lactam 항균제의감수성여부를예측할수있는데 penicillin 최소억제농도가 0.06 μg/ml 이하이면 ampicillin, ampicillin/sulbactam, cefaclor, imipenem 등에도감수성으로해석하며, 2 μg/ml 이하이면 amoxicillin, amoxicillin/clavulanate, cefotaxime, ceftriaxone 등에도감수성으로해석할수있다 [24,25]. Table 2. Empiric antibiotic therapy for community-acquired pneumonia and recommended doses of antibiotics a [1] Outpatient treatment β-lactam (oral) ± macrolide (oral): cefotaxime, ceftriaxone, ampicillin/sulbactam, or amoxicillin/clavulanate ± azithromycin, clarithromycin, erythromycin, or roxithromycin Respiratory fluoroquinolone monotherapy: gemifloxacin (oral), levofloxacin (oral), or moxifloxacin (oral) Inpatient, non-icu treatment, Pseudomonas is not a consideration β-lactam (IV) + macrolide (oral or IV): cefotaxime, ceftriaxone, ampicillin/sulbactam, or amoxicillin/clavulanate + azithromycin, clarithromycin, erythromycin, or roxithromycin Respiratory fluoroquinolone: gemifloxacin (oral), levofloxacin (IV or oral), or moxifloxacin (IV or oral) Inpatient, ICU treatment, Pseudomonas is not a consideration β-lactam (IV) + azithromycin (IV or oral): cefotaxime, ceftriaxone, ampicillin/sulbactam, amoxicillin/clavulanate + azithromycin (IV or oral) β-lactam (IV) + fluoroquinolone: cefotaxime, ceftriaxone, ampicillin/sulbactam + gemifloxacin (oral), levofloxacin (IV or oral), moxifloxacin (IV or oral) Inpatient, ICU treatment, Pseudomonas is a consideration Antipneumococcal, antipseudomonal β-lactam (IV) (cefepime, piperacillin/tazobactam, imipenem, meropenem) + ciprofloxacin or levofloxacin Antipneumococcal, antipseudomonal β-lactam (IV) + aminoglycoside + azithromycin (IV or oral) Antipneumococcal, antipseudomonal β-lactam (IV) + aminoglycoside + antipneumococcal fluoroquinolone (gemifloxacin, levofloxacin, moxifloxacin) a β-lactam (po): amoxicillin 1 g three times daily or amoxicillin/clavulanate 2 g twice daily, cefpodoxime 200 mg twice daily, cefditoren 100 mg twice daily; β-lactam (IV): ceftriaxone 1-2 g q24h, cefotaxime 1-2 g q8h, cefepime 1-2 g q8h or q12h, cefpirome 1-2 g q12h, imipenem 0.5-1 g q8h or q6h, meropenem 0.5-1 g q8h; Macrolid: azithromycin 500 mg on day one followed by four days of 250 mg a day, clarithromycin 250 mg twice daily or clarithromycin XL 1,000 mg once daily, erythromycin 250-500 mg four times daily, roxithromycin 300 mg daily or 150 mg twice daily; Respiratory fluoroquinolone: gemifloxacin 320 mg daily (po), levofloxacin 750 mg daily (po/iv), moxifloxacin 400 mg daily (po/iv). - 692 -
- 김신우. 폐렴의내성과치료 - S. pneumoniae 의 macrolide 내성현황과그임상적의의 S. pneumoniae의 penicillin에대한내성률의증가와더불어 macrolide 에대한내성률증가도임상적으로매우중요하다. 전세계적으로 S. pneumoniae의 macrolide 내성은약 30% 정도이다 [26]. 그러나국내는 erythromycin에대한내성률이 80.6% 로매우높게보고되었다 [13]. 아시아지역의내성이높은데중국, 대만, 베트남등의내성률은 70-90% 내외로보고되었다 [9]. Erythromycin보다뒤에개발되어비교적새로운 macrolide 계열에속하는 azithromycin과 clarithromycin에대한내성률역시각각 77.4%, 74.2% 로높게보고된다 [13]. 국내에서이들의내성기전은 erm (B) 와 mef (A) 유전자에의한다 [27,28]. 이들두유전자를동시에가지기도한다 [27]. 이유전자를가진경우 MIC가 64-128 mg/l 이상인고도내성을나타내는데이는항생제의용량을늘여도도달할수없는농도로 macrolide 단독치료가임상적으로위험함을시사한다. 이로인해 2009년에발표된국내지역사회획득폐렴의치료지침에서는미국이나영국과는달리 macrolide 단독치료의선택을경험적치료에서제외하였다 (Table 2) [1,29,30]. S. pneumoniae 의 quinolone 내성현황과그임상적의의 Quinolone계항생제중늦게개발된 호흡기계퀴놀론계 (gemifloxacin, moxifloxacin, levofloxacin) 는 penicillin 내성 S. pneumoniae에효과적인것으로인정되고있다. 그러나 fluoroquinolone의사용이증가하면서이약제에대한내성균이출현하고있다 [27,31]. S. pneumoniae의 quinolone에대한내성은 DNA gyrase 유전자인 gyra와 topoisomerase IV 유전자인 parc와 gyre의단계적인변이에의한다 [2]. 더불어 efflux를내성기전으로사용하기도하지만 quinolone 고도내성은주로 gyra 및 parc의동시내성에의한다 [2]. 캐나다의경우일찍부터성인에서동정된 S. pneumoniae의 2.9% 가감수성이없는것보고되었다 [31]. 국내에서는 2000-2001년에모인균주를조사한연구에서 gemifloxacin, moxifloxacin, levofloxacin에대한내성은발견되지않았으며, ciprofloxacin 에대한내성률은 6.5% 로보고하였다 [9]. 이후 2002년에서 2006년까지모은 S. pneumoniae 국내균주로시험한보고에서 levofloxacin에감수성이없는균주가 3.8%, moxifloxacin 에감수성이없는균주가 2.1% 로보고되어 [27] 국내에서도내성이증가하고있음을시사하였다. Fluoroquinolone의사용이증가하면서내성률은앞으로계속증가할것으로관심을 기울여야한다 [1,32]. 호흡기용 quinolone 약제의사용시내성의문제외에임상적으로결핵성폐렴을구분하는노력이필요함이강조되고있다 [15,29]. 국내결핵의유병률은 2006년보고자료에의하면인구 10만명당 92명으로아직높은편으로, 지역사회획득폐렴의원인중하나로결핵의가능성을임상의는항상고려해야한다. 지역사회획득폐렴에대해 quinolone을치료제로사용하다가속립성결핵의진단이늦어진보고가있으며 [33] 이는임상에서실제경험할수있는일이다. Quinolone의폐렴에대한 1차적사용은가이드라인에사용할수있는것으로되어있으나 [1] 내성증가문제와결핵에부분적효과를가지는문제가있으므로이부분에대한주의를해서선택하여야한다 [1,29]. 다제내성 S. pneumoniae 와다른치료약제의고려다제내성 S. pneumoniae는세가지계열이상에서내성을가지는 S. pneumoniae를이르며 South Africa 에서 1978년에처음보고되었다 [34]. Penicillin 내성기준의변경으로기존의다제내성 S. pneumoniae에대한보고의해석에어려움이있다. 다제내성 S. pneumoniae는나라별큰차이를내는것으로보고되며내성클론 (clones) 을전달함으로서전파된다 [32]. Vancomycin이나 linezolid는 S. pneumoniae에감수성을가진다 [2,27,35]. β-lactam에과민반응을일으킨병력에서고려할수있으며 1차적으로고려할약제는아니다. 첫 ketolide 계열 (macrolide 에서유도 ) 의항생제인 telithromycin 은국내유통이되고있고다제내성 S. pneumoniae에효과적이다 [36,37]. 또한 H. influenzae, Moraxella catarrhalis, C. pneumoniae, Legionella pneumophila 및 M. pneumoniae 에도감수성을가져서 penicillin 내성이많이강조되던때큰주목을받았으나목숨을위협하는간독성이보고된 [38] 이후사용이주춤하며임상연구결과도잘나오지않고있다. 최근 methicillin 내성 Staphylococcus aureus에효과를가진 cephalosporin인 ceftobiprole과 ceftaroline도 S. pneumoniae 에매우좋은항균력을가진다. Ceftaroline은 penicillin, amoxicillin 및 cefotaxime 에내성을보이는균주에대해서도 MIC 90 (90% 균주의 MIC) 이 0.5 mg/l 정도를보였고 [39,40], 최근동물실험에서도좋은효과를보였다 [41]. 향후국내에서 ceftaroline 의사용이가능할때 1차적으로사용하지는않겠지만좋은선택의하나가될수있을것으로생각된다. - 693 -
- The Korean Journal of Medicine: Vol. 81, No. 6, 2011 - Tigecycline은첫 glycycycline 계열 (tetracycline에서유도 ) 약물로국내에서다제내성 Acinetobacter 감염으로인해그사용이많아지고있다. Tigecycline은 methicillin 내성 S. aureus에도실험실적감수성을보이는광범위항생제로복강내감염과복잡성피부및연조직감염에허가가나있다. 대부분의 S. pneumoniae가 MIC 0.25 mg/l를보인다 [2]. 지역사회획득폐렴의치료에서 levofloxacin 과유사한효과를보였다 [42-44]. 그러나폐렴에는아직미국식품의약품안전청과국내에서허가가되어있지는않으며가이드라인들도사용을권하고있지않다 [1,4]. 이는지역사회획득폐렴이나병원획득폐렴등에대한자료의부족때문으로생각된다. 예방접종을통한 S. pneumoniae 내성의극복내성의시대에가장효과적인대책중하나는예방접종의활성화이다 [45]. S. pneumoniae에대한 heptavalent protein conjugate vaccine (PCV7: for 6A, 6B, 9V, 14, 19A, 19F and 23F) 은 6세미만에서침습성폐알균감염증 (invasive pneumococcal diseases: IPD) 을일으키는균주의 80% 를극복할수있다 [2]. 이백신은소아와성인연령에까지 IPD의감소에매우효과적임이여러연구에서증명되었다 [46-48]. 그러나 PCV7 에포함되지않는혈청형 ( 특히 19A) 균주에의한감염의증가가보고되었다 [49]. 국내에서도 2003년하가되어사용되기시작되었으며같은현상이관찰되었다 [50]. PCV7 은백신에서벗어나는혈청형의증가를가져오기는하지만전체적인 IPD의감소를가져왔다 [47]. PCV7 은국내에서상품명 Prevenar 로판매되고있으며최근개발된 10-valent pneumococcal conjugate vaccine (PCV10: 1, 4, 5, 6B, 7F, 9V, 14, 23F tetanus toxoid conjugate serotype: 18C, diphtheria conjugate serotype: 19F) 및 13-valent pneumococcal conjugate vaccine (PCV13: 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 3, 5, 6A, 7F, 19A) 도국내에서 2010년 3월허가를얻었다. PCV10 은 Synflorix, PCV13 은 Prevenar 13 으로출시되어사용되고있다. 이들의사용이증가됨에따라향후 IPD의감소와혈청형의변화가국내를포함한전세계에서기대된다 [51]. 성인에게사용되는다당질백신 (polysaccharide vaccine) 은국내에 Pneumo 23 과 Prodiax 가유통되며그사용이더욱활성화될필요가있다. 2010년국내조사에서 65세이상 1,097명의성인중 9명이예방접종을받아 0.8% 의접종률보고를하였다 [52]. 이를볼때임상의가예방가능한질환에 대한예방접종을더욱적극적으로권유할필요가있다고생각된다. Mycoplasma의항생제내성 M. pneumoniae는지역사회획득폐렴의흔한원인균으로세포내기생을하는세균이다. 이세균은세포벽이없으므로세포벽을공격하는 β-lactam 항생제등에자연내성 (intrinsic resistance) 을나타낸다. 이균에대해서는세포내농도가좋은 macrolide, tetracycline, quinolone 등을사용하여왔다. 그러나 2000년대이후 macrolide 내성이유럽과미국과중국, 일본등에서보고되고있다 [5-7]. 또한전세계적증가가보고되어있으며더문제가될것이다 [7]. 최근중국에서 67균주중 46균주 (69%) 에서 macrolide 내성을보인것을보고하였으며이들은임상적으로더긴치료기간을필요로하였다고한다 [53]. 중국에서의균주중 90% 이상에서 macrolide 내성을보인보고도있다 [6]. 내성기전은 23S 리보좀 (ribosomal) RNA 유전체의점변이 (point mutation) 이다 [53]. 국내연구는아직이부분에서없지만전세계적 macolide 에대한내성증가와특히지역적으로가까운중국의내성을고려할때국내도충분히가능하며국내자료가필요한상황이다. Haemophilus influenzae 의항생제내성 H. influenzae 의 β-lactam 항생제에대한내성은분해효소인 β-lactamase를생산함으로나타내며내성률이증가하고있다 [10,54,55]. 국내에서도그증가가보고되고있다 [56-58]. 국내에서 2002년에서 2004년에확보된균주를시험한 Bae 등의보고에서 ampicillin에대한내성은 57%, cefaclor에대해서는 46% 의내성을보였다. β-lactamase 저해제를붙인 amoxicillin/clavulanate에는 99% 감수성, cefotaxime 과 imipenem 에는각각 99% 91% 의감수성을보인것으로보고된다 [57]. 그러나이국내균주들은 azithromycin과 ciprofloxacin에는모두감수성을보였다. 2005년에서 2006년에확보된균주를시험한 Bae 등의보고에서는내성률이다음과같았다 : ampicillin 58.5%, cefuroxime 23.3%, clarithromycin 18.7%, cefaclor 17.0%, amoxicillin-clavulanate 10.4% [58]. H. influenzae 의원인균으로서의보고는국내에서는매우적은빈도를보이는데균주배양의어려움등이관여될것으로생각된다. 실제로 H. influenzae 가폐렴의주요원인균의하나로생각되므로이균이원인균으로동정된경우 H. influenzae 의내성을고려할 - 694 -
- Shin-Woo Kim. Resistance and treatment of pneumonia - 때 ampicillin을사용하기보다 amoxicillin/clavulanate나 ampicillin/ sulbactam 또는 3세대 cephalosporin의사용이합리적인선택으로판단된다. 국내외가이드라인에서도이를반영하여권유되고있다 [1,4]. 그러나 H. influenzae 의실험실적 β-lactam 및 macrolide 내성이임상적으로어떤의미를가지는지에대한자료는매우적다. 일부동물실험연구와사람에대한소규모관찰연구에서내성의임상적의미는크지않을것으로보고한바있다 [55,59]. 이분야에있어잘통제된임상연구가나오기를기대하나쉽지는않을것같다. 지역사회폐렴을일으킨그람음성균의항생제내성그람음성균이지역사회획득폐렴의원인이되는비율을국내자료는국외보다비교적높은빈도를보고하고있다 [1]. 이는 3차병원위주의연구와연관된가능성이많으며이경우의료관련폐렴 (healthcare-associated pneumonia) 을완전히배제하지못할가능성과연관된듯하다. 그러나지역사회획득폐렴에서 P. aeruginosa, E. coli, K. pneumoniae 등은전통적으로원인이되어왔다 [1]. 그람음성균에의한지역사회획득폐렴의위험요인으로는기저질환을가진사람등으로그예후가나쁜것으로알려져있다 [60-62]. 최근 Acinetobacter 에의한지역사회획득폐렴도보고되고있다 [63-65]. 그람음성균에의한지역사회폐렴에서원인균의내성이미치는영향에대한연구는아직찾아보기힘들다. 그람음성균의내성문제가증가되는현시점에서고령화와기저질환자의증가와더불어향후더문제가될수있을것이다. 항생제내성문제의극복을위한방안불필요한광범위항생제의사용은우리가현재경험하고있는바와같은항생제내성문제를유도한다. 이런현상을항생제의사용에따른 collateral damage ( 의도하지않았지만발생하는피해라는의미로사용 ) 로설명이많이되고있다. 광범위항생제의 선택적압력 (selective pressure) 은 S. pneumoniae와다른폐렴의원인균들의내성을유도할것이분명하다. 우리세대와다음세대를위해지혜로운적합한항생제사용을위한방안들이모든의사와국민의관심이되어야할상황이다. WHO (World Health Organization) 는 2011년 World Health Day 에 Antimicrobial resistance: no action today, no cure tomorrow 를표어로발표하고전세계의내성극복을 위한노력을다시촉구를하고있다 [66]. 국내에서도항생제내성을극복하는노력들이필요한데이에대한그방안들을대별하면 1) 효과적인항생제치료, 2) 예방접종, 3) 병원감염관리, 4) 적절한정책과보건시스템등이필요하다 [45]. 여기에더하여의료기관은항생제관리 ( antibiotic stewardship ) 의실천이필요하고, 국민은부적절한항생제사용의요구자가아니라견제자가될수있도록교육과홍보가필요하다. 최근감염전문가들이 항생제올바로쓰기캠페인 등을하고국민들이이해하기쉬운홍보자료등을통해교육하는활동이있는것은고무적이며많은의료인의동참이필요하다. 결론지역사회획득폐렴의흔한원인균은 S. pneumoniae, M. pneumoniae, H. influenzae 등이다. S. pneumoniae의 penicillin에대한항생제내성은중요한사안으로여겨졌으나 penicillin계약물의사용이임상적실패를가져오지않는자료들과항생제약력학 / 약동학지식을적용하여 2008년 1월내성판정기준의변경하였고이로인해새기준을적용하는경우뇌수막균의원인이아닌 S. pneumoniae는전세계적으로낮은내성률을보이게되었다. S. pneumoniae에대해서는 penicillin계약물도사용가능할것으로생각되지만 3세대 cephalosporin 사용이익숙한임상의들에게그사용이활성화되어있지는않다. S. pneumoniae 의 macrolide 내성은국내에서매우흔하고고도내성을나타내므로임상적실패가우려되고국내가이드라인은이를고려하여경험적치료로 macrolide 를단독으로사용하는것을배제하고있으며이는합리적이다. 그러나 macrolide 내성의임상적의미에대한자료가더있기를기대한다. S. pneumoniae 의 quinolone 내성은아직낮고가이드라인에서외래에서의 1차적치료에사용할수있다고기록하고있다. 그러나사용과함께내성의증가가우려되고 1차적치료시국내에서는결핵의가능성에대한관심을두고이를고려하여선택을결정하는것이필요하다. Mycoplasma의 macrolide 항생제내성은그보고가증가하고있으나국내자료는찾아보기어렵고임상적으로치료기간을길게하여야했던보고가있으나더자료가필요하다. H. influenzae 의 β-lactam 항생제내성은 β-lactamase를생산함으로나타내며국내에서도 ampicillin, cefaclor 등에반정 - 695 -
- 대한내과학회지 : 제 81 권제 6 호통권제 616 호 2011 - 도에서내성을보여이균이원인균인경우 β-lactamase 저해제를붙인 amoxicillin/clavulanate, 좀더안정정인 cefotaxime, ceftriaxone 등의사용이적절함을보여준다. 그람음성균에의한지역사회획득폐렴에서항생제내성의임상적의미는잘연구된바가없으나그람음성균의내성이증가하고있어향후우려의대상이될수있을것이다. 지역사회획득폐렴의내성문제는다른감염질환의내성문제와동일하게효과적인항생제치료, 예방접종, 적절한병원감염관리, 적절한정책과보건시스템, antibiotic stewardship 및국민들의항생제올바로쓰기에대한인식증가등의다각적접근이필요하며임상의는치료뿐아니라이러한부분에도관심을기울이는것이필요하다. 특히폐알균백신의예방접종을활성화하는것이절실히필요하다. 이미나와있는근거중심의학 ( 국내가이드라인및외국가이드라인등 ) 적권유는내성문제, 향후내성의유도문제, 경제성등을고려하고있으며, 가이드라인이원인균내성의변화와함께개정될것이다. 가이드라인을따를때좋은예후를보이는것은잘증명이되어있으므로이의적극적인적용이확산되는것이필요하다. 중심단어 : 지역사회획득폐렴 ; 항생제내성 ; 항생제치료 REFERENCES 1. Song JH, Jung KS, Kang MW, et al. Treatment guidelines for community-acquired pneumonia in Korea: an evidencebased approach to appropriate antimicrobial therapy. Infect Chemother 2009;41:133-153. 2. Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumoniae resistance: implications for therapy of community-acquired bacterial pneumonia. Int J Antimicrob Agents 2010;36:197-204. 3. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA 1996;275:134-141. 4. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of communityacquired pneumonia in adults. Clin Infect Dis 2007; 44(Suppl 2):S27-S72. 5. Cardinale F, Chironna M, Dumke R, et al. Macrolideresistant Mycoplasma pneumoniae in paediatric pneumonia. Eur Respir J 2011;37:1522-1524. 6. Bébéar C, Pereyre S, Peuchant O. Mycoplasma pneumoniae: susceptibility and resistance to antibiotics. Future Microbiol 2011;6:423-431. 7. Morozumi M, Iwata S, Hasegawa K, et al. Increased macrolide resistance of Mycoplasma pneumoniae in pediatric patients with community-acquired pneumonia. Antimicrob Agents Chemother 2008;52:348-350. 8. Lee HJ, Park JY, Jang SH, Kim JH, Kim EC, Choi KW. High incidence of resistance to multiple antimicrobials in clinical isolates of Streptococcus pneumoniae from a university hospital in Korea. Clin Infect Dis 1995;20:826-835. 9. Song JH, Jung SI, Ko KS, et al. High prevalence of antimicrobial resistance among clinical Streptococcus pneumoniae isolates in Asia (an ANSP study). Antimicrob Agents Chemother 2004;48:2101-2107. 10. Hoban DJ, Doern GV, Fluit AC, Roussel-Delvallez M, Jones RN. Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin Infect Dis 2001; 32(Suppl 2):S81-S93. 11. Song JH, Lee NY, Ichiyama S, et al. Spread of drug-resistant Streptococcus pneumoniae in Asian countries: Asian Network for Surveillance of Resistant Pathogens (ANSP) Study. Clin Infect Dis 1999;28:1206-1211. 12. Baquero F. Pneumococcal resistance to beta-lactam antibiotics: a global geographic overview. Microb Drug Resist 1995;1: 115-120. 13. Jung SI, Kim NY, Son JS, et al. Changing trends in antimicrobial resistance among invasive pneumococcal pathogens in Asian countries: Asian Network for Surveillance of Resistant Pathogens (ANSP) Study. Infect Chemother 2004;36:1-10. 14. Cheong HJ, Hwang BY, Park CW, et al. Clinical and genetic characteristics of infection by penicillin-resistant Streptococcus pneumoniae from community and hospital. Korean J Infect Dis 2001;33:112-122. 15. Pallares R, Liñares J, Vadillo M, et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995;333:474-480. 16. Pallares R, Capdevila O, Liñares J, et al. The effect of cephalosporin resistance on mortality in adult patients with nonmeningeal systemic pneumococcal infections. Am J Med 2002;113:120-126. 17. Yu VL, Chiou CC, Feldman C, et al. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 2003;37:230-237. 18. Song JH, Jung SI, Ki HK, et al. Clinical outcomes of pneumococcal pneumonia caused by antibiotic-resistant - 696 -
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