병원약사회지 (2018), 제 35 권제 4 호 J. Kor. Soc. Health-syst. Pharm., Vol. 35, No. 4, 391 ~ 399 (2018) https://doi.org/10.32429/jkshp.2018.35.4.001 Original Article 원내폐렴진료지침수립후경험항생제선택의적절성평가 강지영 a, 김형숙 a, 정영미 a, 남궁형욱 a, 이은숙 a, 김은경 b, 황주희 c, 송경호 c, 김의석 c,, 김홍빈 c 분당서울대학교병원약제부 a, 서울대학교약학대학 b, 분당서울대학교병원감염내과 c Evaluation of the Appropriateness of Empirical Antibiotic Prescription after Implementation of Antibiotic Treatment Guidelines for Pneumonia in a Hospital Jiyoung Kang a, Hyungsook Kim a, Youngmi Jeong a, Hyungwook Namgung a, Eunsook Lee a, Euni Lee b, Joohee Hwang c, Kyoungho Song c, Eusuk Kim c, and Hongbin Kim c Department of Pharmacy, Seoul National University Bundang Hospital 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seoungnam-si, Gyeonggi-do, 13620, Republic of Korea a College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea b Geriatric Center, Seoul National University Bundang Hospital 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seoungnam-si, Gyeonggi-do, 13620, Republic of Korea c Background : The Antimicrobial Stewardship Program promotes interdisciplinary interventions and targeted recommendations for the proper utilization of antibiotics. In particular, the aim of the program is to avoid indiscriminate use of broad-spectrum antibiotics based on the documented literature on the significant impact of unsystematic usage of antibiotics on the distribution of antibiotic-resistant microorganisms. To improve the care process for pneumonia treatment using antimicrobial agents, institution-level guidelines were established and disseminated at the Seoul National University Bundang Hospital in April 2016. In this study, we evaluated changes in the physicians antibiotic prescribing patterns both before-and after-the implementation of the guidelines. Methods : The electronic medical records of inpatients who were prescribed with one or more antibi- 투고일자 2017.9.12; 심사완료일자 2017.11.30; 게재확정일자 2018.9.14 교신저자김의석 Tel:031-787-7062 Fax:031-787-4052 E-mail:eskim@snubh.or - 391 -
JKSHP, VOL.35, NO.4 (2018) otics in May 2014 (Group A) and May 2016 (Group B) were reviewed. Data on demographic characteristics, clinical outcomes, and antibiotic prescriptions were collected and the prescription records were compared both before- and after- the implementation of the guidelines. Results : A total of 180 patients were included in the study: 77 patients in group A and 103 patients in group B. The baseline characteristics of the patients were not significantly different between the two groups. Community-acquired pneumonia was the most common diagnosis in both the groups and the difference was not significant (68.8% vs. 67.9%; p=0.67). The type of antibiotic prescriptions used for empirical treatment was not different between the two groups. The most commonly prescribed empirical antibiotics were cephalosporins, with no significant difference (p=0.31). One of the most inappropriately used antibiotics was piperacillin/tazobactam and the rate of prescription was similar in both the groups (p=0.68). The rates of appropriate empirical selection of antibiotics remained unaltered between the two groups (67.5% vs. 71.8%; p=0.53). Conclusions : Implementation of the guidelines only exhibited no significant effect on the antibiotic prescribing patterns of physicians for the treatment of pneumonia. To improve the adequate use of empiric antibiotics, more active interventions and closer monitoring of the feedbacks should be additionally considered and evaluated in future studies. [Key words] Antimicrobial stewardship program, Piperacillin/tazobactam, Pneumonia 원내진료지침수립을통해적절한항생제사용을유도하는것은항생제적정사용프로그램 (Antimicrobial stewardship program, ASP) 의중요한요소중하나이다. 1) 원내진료지침과같은중재가의사들의항생제처방에미치는효과를평가하는다양한연구가보고되고있다. 2)-4) Green D 등은원내항생제감수성검사결과를바탕으로병원획득폐렴의초기항생제선택을위한원내진료지침을수립하였고, 이를도입하여초기항생제선택의적절성을개선할수있음을확인하였다. 2) Cathy L 등은병원획득, 기계환기관련, 의료관련폐렴의진료지침을수립하고적용하여폐렴치료결과의개선과치료비용의감소를가져오는결과를얻었고, 중환자실재원기간의감소도확인하였다. 4) 특히광범위항생제의적절한사용은항생제내성균발현방지와치료결과에큰영향을미치기때문에원내진료지침수립에반드시고려되어야할중재항목이다. Piperacillin/tazobactam은그람양성균, 그람음성균, 혐기균에감수성을가진광범위항생제로부적절 한사용은장기적으로원내항생제내성균증가를초래할가능성이많다. 5) 또한특정항생제의사용증가가항생제내성균발생을증가시킨다는연구결과를고려하였을때 piperacillin/tazobactam과같은광범위항생제의적절한사용이매우중요하다. 6) 분당서울대학교병원 (SNUBH) 에서는항생제적정사용을위한항생제관리팀을설립하여운영중이다. 7),8) 최근폐렴치료를위한원내 piperacillin/tazobactam 사용량이증가함에따라국내폐렴원인균과내성률을고려하여광범위항생제인 piperacillin/tazobactam 을임상적으로필요한경우에만제한하여사용하여야한다는필요성이대두되었다. 이에 SNUBH 항생제관리팀에서는폐렴진료지침을새로수립하여권고하였다. 이연구를통해폐렴진료지침수립이의사들의초기경험항생제선택에미치는영향을분석하고자하였다. 연구방법 - 392 -
강지영 : 원내폐렴진료지침수립후경험항생제선택의적절성평가 Seoul National University Bundang Hospital Antimicrobial agents for Pneumonia Manual Division of Infectious Diseases Review Date; April 30. 2016 A. 임상소견 + 영상의학적소견 - 임상소견 : 발열, 화농성객담, 백혈구증가증 - 영상의학적소견 : 새롭게발생한폐침윤 B. 미생물학적진단혈액배양외에적절한호흡기계검체를반드시획득하여그람염색및배양기관지내시경이가능하다면시행 (Bronchial washing or Bronchoalveolar lavage) 기관지내시경시행이어려울경우기관절개가되어있다면경기관흡인 (Transtracheal aspirate) 기관절개가되어있지않다면적절한객담채취 (Sputum) C. 중증여부판단 - 중증폐렴의정의 : 호흡부전이발생하여기계환기를요하는경우혈압저하, 다장기부전등패혈증의소견을보이는경우 D. 다제내성균위험성평가 - 다제내성균의정의 : Methicillin-resistant staphylococcus aureus, Vancomycin-resistant enterococcus, Extended spectrum beta lactamase producing Gram negative bacilli, Carbapenem resistant enterobacteriaceae, Multi drug resistant -acinetobacter, Multi drug resistant-pseudomonas - 고위험군 : 최근 90일사이에다제내성균이분리된적이있는경우최근 90일사이에광범위항생제를투약한적이있는경우 - 중증도내지저위험군 : 병원입원이후 5일이후발생한폐렴최근 90일사이에입원한적이있는경우유지투석을하고있는경우면역억제치료혹은항암치료를받고있는경우요양병원혹은요양원에거주중인경우 E. 초기항생제선정 - 중증폐렴혹은다제내성균고위험군인경우 1st agent 중단독사용을우선고려하되, 중증이라면 2nd agent 까지병합고려 1st agent : Piperacillin/tazobactam or cefepime or carbapenem (imipenem, meropenem) 2nd agent : Amikacin, ciprofloxacin, levofloxacin - 그외의경우특별한이유가없다면다음항생제중단독사용 Ceftriaxone, Cefotaxime, Moxifloxacin, Levofloxacin F. 추적관찰및재평가 - 초기항생제시작후 3~4 일사이재평가 : 임상적호전여부, 초기배양검사결과 - 배양검사에서균이동정된경우 : 항생제감수성결과에맞추어항생제변경 - 배양검사에서균이동정되지않은경우 : 임상적호전을보인다면보다범위가좁은항생제로변경고려임상적호전이없다면기관지내시경혹은검사등환자에따라추가계획수립 Fig. 1 Guideline for antibiotic therapy in pneumonia in Seoul National University Bundang Hospital - 393 -
JKSHP, VOL.35, NO.4 (2018) 1. 지침수립과배포 SNUBH 폐렴진료지침 은분당서울대학교병원감염내과의사와약사로구성된항생제관리팀이참여하여수립하였다. 본진료지침은기존에알려진국내외폐렴원인균의분포와내성균위험인자관련자료를바탕으로 2016년 4월말에수립되었다 (Fig. 1). 폐렴환자를가장많이진료하고있는내과의사를대상으로감염내과에서진료지침을배부하여 2016년 5월부터지침에따라초기경험항생제의처방을하도록권고하였다. 병원차원의지침배포와권고이외전산기반의실시간처방중재혹은기타교육프로그램제공등은시행하지않았다. 2. 연구대상원내진료지침수립전인 2014년 5월과진료지침수립후인 2016년 5월각각한달씩을연구기간으로선정하였다. 중동호흡기증후군의확산이있었던 2015 년의사례는의사들의초기경험항생제선택에외부적인영향이추가적으로있었을가능성이높아서연구에포함하지않았다. 대상환자의선정은연구기간동안분당서울대학교병원호흡기내과에입원한환자의퇴원시진단명코드 (ICD10) 를검색하여폐렴유무를확인하였고입원기간중항생제처방을받은모든환자를포함하였다. 항생제를투여하지않은경우는제외하였다. 3. 자료수집항목대상환자의성별, 나이, 기저질환, 폐렴의발생장소, 재원기간, 병원내사망여부, 초기경험항생제의종류와사용기간등의임상정보는의무기록을통하여수집되었다. 병원획득폐렴은입원이전에폐렴의임상소견이없었던사람이입원후 48 시간이지나고나서병원환경에서발생한폐렴으로정의하였다. 의료관련폐렴은지역사회혹은병원입원 48시간이내에폐렴이발생하였지만최근 90일이내에 2일이상의입원, 만성질환을앓는노인들을위한전문요양시설수용인, 최근 30일이내에항균제나항암제투여, 또는창상치료를받은적이있는경우, 최근 30일이내에병원을 방문하였거나혈액투석중인환자에게발생한폐렴으로정의하였다. 9) 병원획득폐렴중기계환기관련폐렴은기계환기시작시점에는폐렴이나혹은폐렴의잠복기에있지않은환자가기관삽관이나기계환기를시작한후 48 시간이후에폐렴이발생한경우로정의하였다. 10) 병원획득또는의료관련폐렴의위험인자가없는경우는지역사회획득폐렴으로정의하였다. 호흡기계검체 ( 객담, 경기관흡인액, 기관지세척액등 ) 를통한미생물검사결과에서동정된미생물에대한자료를수집하였다. 초기경험항생제는폐렴진단후해당환자에게 24 시간이상투여된첫항생제로정의하였고, 항생제를병합하여사용한경우에는투여된항생제를모두초기경험항생제로하였다. 폐렴의추정원인미생물은폐렴진단이후경험항생제가들어가기전에시행된호흡기계검체배양검사중가장처음으로세균이동정된결과로하였다. 항생제가투여된이후에시행된배양검사결과는제외하였다. 4. 항생제적절성평가초기항생제적절성여부는 SNUBH 폐렴진료지침 (Fig. 1) 에따른임상소견, 중증여부및다제내성균위험성평가를기반으로평가하였다. 중증폐렴혹은다제내성균고위험군의경우지침에서권고하는 1차약제인 piperacillin/tazobactam, cefepime, carbapenems 중한가지약제사용또는중증폐렴에서 2 차약제인 amikacin, ciprofloxacin, levofloxacin을병용하여처방한경우를적절한것으로평가하였다. 그외다제내성균고위험군이아닌경우지침에서권고되는 ceftriaxone, cefotaxime, moxifloxacin, levofloxacin을단독사용한경우적절한처방으로평가하였다. 지역사회획득폐렴에서 cephalosporin계항생제와 macrolide 항생제를병용한경우도적절한처방으로평가하였다. 5. 통계분석통계분석은 IBM SPSS ver.21을사용하여변수에따라 T- 검정과카이제곱검정혹은 Fisher의정확한검 - 394 -
강지영 : 원내폐렴진료지침수립후경험항생제선택의적절성평가 Table 1 Baseline characteristics of patients Characteristics Before implementation (N=77) After implementation (N=103) p value Male/Female (N) 53/24 66/37 0.51 Age (year, mean±sd) 73.5±15.3 72.5±12.6 0.34 Charlson cormorbidity index score 1.36±1.51 1.87±1.59 0.26 Types of pneumonia [N(%)] Community-acquired pneumonia 53 (68.8) 70 (68.0) Hospital-acquired pneumonia 22 (28.6) 28 (27.2) Hospital-acquired pneumonia without ventilator 2 (2.6) 3 (2.9) 0.67 Ventilator-associated pneumonia 0 (0) 2 (1.9) 정을시행하였다. p값이 0.05 미만인경우를통계적으로유의한것으로정의하였다. 본연구는분당서울대학교병원의기관윤리심의위원회 (Institutional Review Board, IRB) 로부터승인을받았다.(IRB No. B1609/361-112) 연구결과 1. 환자군기본특성 SNUBH 진료지침수립전인 2014년 5월에폐렴으로입원하여항생제처방을받은건수는 77건이었고, 지침수립후인 2016년 5월에는 103건으로총 180건의사례를분석하였다. 지침수립전과후두군간에성별과평균나이에유의한차이는없었다. 두군모두지역사회획득폐렴이가장높은비율로관찰되었고, 의료관련폐렴, 기계환기를받지않은병원획득폐렴, 기계환기관련폐렴순의빈도를보였고, 분포는두군에서유의한차이를보이지않았다. Charlson comorbidity index score는두군간유의한차이를보이지않았다 (Table 1). 2. 추정원인미생물분석원인미생물확인을위한배양검사를시행하지않았 거나, 검사를시행하였으나미생물이동정되지않은경우는지침수립전 46 건 (59.7%), 수립후 60 건 (58.3%) 이었다. 항생제투여후시행된호흡기계배양검사에서미생물이동정된경우는지침수립전 14 건 (18.2%), 수립후 18 건 (17.5%) 이었고, 추정원인미생물에포함하지않았다. 최종적으로지침수립전 77건중 31건 (40.1%), 수립후 103건중 43건 (41.7%) 에서미생물이동정되었다. 추정원인미생물의분포는두군에서통계적으로유의한차이는없었다 (p=0.08). 양군모두비다제내성균이다제내성균보다더높은빈도를보였고, 광범위항생제의사용이필요한다제내성균의경우수립전 3건 (3.9%), 수립후 5건 (4.9%) 으로큰차이는없었다 (Table 2). 3. 경험항생제의적절성평가초기경험항생제는폐렴진료지침수립전후모두에서 cephalosporin [( 전, 후 ), (31%, 36.6%)] 이가장높은빈도를보였고, 다음으로 fluoroquinolone (26.7%, 21.6%), piperacillin/tazobactam (21.6%, 19.6%), macrolide (11.2%, 18.3%), carbapenem (3.4%, 3.3%) 순이었다 (Fig. 2). 진료지침수립후 piperacillin/tazobactam과 carbapenem의사용이다소감소하였지만통계적으로유의하지않았고전체적으로초기경험항생제의선택에큰변화를보이지않았다. 부적절한처 - 395 -
JKSHP, VOL.35, NO.4 (2018) Table 2 Distribution of identified microorganisms in respiratory specimens before administration of antibiotics Organisms Before implementation (N) After implementation (N) Staphylococcus aureus 5 4 MRSA* 2 2 Klebsiella pneumoniae 3 5 ESBL (+) K. pneumoniae 0 1 Pseudomonas aeruginosa 4 1 MDR -P. aeruginosa 0 0 Haemophilus influenzae 0 0 Acinetobacter baumannii 2 2 Streptococcus pneumoniae 0 3 Others 4 10 *MRSA : Methicillin-resistant Staphylococcus aureus ESBL : Extended spectrum beta-lactamase MDR : Multi-drug resistant Streptococcus agalactiae, Escherichia coli, β-hemolytic streptococci, Serratia marcescens Bacilus species, Enterobacter, methicillin-resistant coagulase negative staphylococci, Moraxella catarrhalis, Providencia stuartii, Klebsiella oxytoca, Proteus mirabilis, Enterococcus faecium, Pneumocystis jirovecii, Raoultella species Fig. 2 Distribution of empirical antibiotic choice before and after implementation of antibiotic treatment guideline for pneumonia - 396 -
강지영 : 원내폐렴진료지침수립후경험항생제선택의적절성평가 Table 3 Appropriateness of empirical antibiotic choice before and after implementation of antibiotic treatment guideline for pneumonia Before implementation (N=77) After implementation (N=103) Total Appropriate 52 (67.5%) 74 (71.8%) Inappropriate 25 (32.5%) 29 (28.2%) Piperacillin/tazobactam Appropriate 17 23 Inappropriate 8 7 Carbapenems Appropriate 3 1 Inappropriate 1 0 Prescription single antibiotic 38 (49.4%) 53 (51.5%) Prescription combination antibiotic 39 (50.6%) 50 (48.5%) p value 0.53 0.68 1.00 0.72 방의사유는다제내성균고위험군이아닌환자에게 piperacillin/tazobactam을사용한경우혹은중증폐렴으로평가되지않은환자에게 2가지이상항생제를병용한경우등이흔했다. 지침수립전 77 건처방중두가지항생제를병합하여처방한경우는지침수립전 50.6%(39/77건 ) 이었고, 지침수립후 48.5% (30/ 53건 ) 으로두군간유의한차이가없었다 (p=0.72). 진료지침에근거한항생제처방적절성은지침수립전 67.5%(52/77건 ), 지침수립후 71.8%(74/103건 ) 으로큰차이가없었다 (p=0.53). Piperacillin/tazobactam 및 carbapenem의처방적절성또한지침수립전, 후로차이가없었다 (Table 3). 고찰지역사회획득폐렴의초기항생제적절성개선을위한항생제관리팀활동의효과를분석한 Ostrowsky의연구에서는다학제항생제관리팀의적절한항생제선택을위한정보제공, 지역사회획득폐렴에적절한항생제및용량선택을위한알고리즘수립등의활동을통해초기항생제치료의적절성에개선을확인하였다. 11) 또한항생제관리팀활동의일환으로특정질병에대한원내진료지침의수립의효과를분석한 Jenkins TC 등의연구에서도초기항생제선택적절성의향상이확인된바있다. 12) 이를바탕으로다학제적인항생제관리팀활동의일환으로써원내에서사용될수있는수많은항생제를특정질환에가장적절한항균범위를갖는최적경험항생제로범위를좁혀, 원내에적합한진료지침수립을통해관리하는것이효과적일수있음을알수있다. 본연구에서저자들은폐렴에대한항생제적정사용을목표로국내폐렴원인균및임상적상황을고려한원내진료지침을수립하였고항생제관리팀에의한초기항생제사용선택의적절성개선및부적절한광범위항생제사용의감소를보고자하였다. 본진료지침은환자의임상적, 역학적소견, 폐렴의중증도, 다제내성균위험요인과과거다제내성균감염여부등을평가하여초기항생제를선택하도록권고하였다. 진료지침의수립과도입이후약사의적극적인중재와지속적인교육활동은시행하지않았다. 그결과진료지침의수립과도입만으로는의사의항생제처방에큰영향을미치지않았음을확인할수있었다. 초기적절한항생제선택지연이항생제세균의내성발현가능성을높이며, 13) 적절한항생제를선택함으로써환자의임상적개선을극대화하고내성균발생을최소화할수있다. 14) 특히광범위항생제의부적절한사용은다제내성균발생및감염의위험을증가시킨 - 397 -
JKSHP, VOL.35, NO.4 (2018) 다. 15) 본연구에서는다제내성균에의한고위험군이아닌폐렴환자에게광범위항생제중하나인 piperacillin/ tazobactam을초기경험항생제로선택한경우를확인하였을때에진료지침의수립만으로는부적절한사용의유의한감소를확인할수없었다. 양군에서추정원인미생물중내성균의분포는지침수립전후에큰차이를보이지않았기때문에연구기간에폐렴의원인미생물내성이증가하였을가능성은낮을것으로보인다. 지침의효과를분석한이전연구의결과 2)-4) 에비해본연구에서는진료지침도입후항생제사용률에유의한변화를확인할수없었다. 이는본연구는지침수립직후 1개월을연구기간으로수행하여연구대상수가적은한계점에기인한것으로사료된다. 그러나더중요한요인은항생제관리팀의적극적인중재활동을포함하지않은단순진료지침의수립과배포만으로는의사들의항생제처방적절성을개선하는데그영향이크지않았기때문일것으로보인다. 또한초기경험항생제선택에가장중요한역할을하는전공의의순환근무로인해원활한의사소통과진료지침수립배경및지침준수에대한홍보의연속성을확보하지못한것이장애요인이었을것으로보인다. 따라서항생제관리팀활동의일환으로국내임상적상황을고려한원내진료지침의수립이후에도지속적인중재가필요하다. 효과적인중재를위하여전문적으로항생제처방을모니터링하고의료진에게피드백을담당할약사를포함한항생제관리팀의역할이매우중요할것이다. 적극적인원내항생제관리팀의활동을통해항생제처방적절성, 치료성적의개선을얻을수있고, 16) 항생제투여시점및항생제사용기간등항생제사용적절성의개선에도기여할수있을것으로사료된다. 17) 여러메타연구에서도항생제관리팀의교육활동, 감수성에따른항생제선택과중재, 적절한제형으로의변경등의활동을통해입원환자의과도한항생제처방과내성균감염을감소시키며, 효과적인처방을통해치료성적의개선을보였다. 18) 본연구결과를해석하는데몇가지제한점이있다. 첫째로본연구는지침수립후폐렴환자의임상적치료효과의개선에대해분석하지못하였다. 둘째로추정원인미생물의경우검체의적절성에대한평가가이루어지지않아동정된균이실제폐렴의원인균이아니었 을가능성이있다. 그러나다학제적인항균제관리팀의역할과원내항생제처방지침이적절한항생제사용에미치는영향에대한국내연구가부족한실정으로, 국내의임상적상황을고려한원내진료지침수립후의사들의항생제처방에대한효과를분석하고항생제관리팀의적극적중재활동의필요성을확인하였다는데본연구의의의가있다. 결론항생제관리팀활동의일환으로원내진료지침의수립이항생제사용개선에영향을미칠수있다고알려져있으나, 진료지침수립만으로항생제적정사용의유의한개선은어려울것으로사료된다. 따라서원내진료지침의수립과함께지속적의료진교육, 원내진료지침에따른처방모니터링과피드백등추가적인중재활동이필요하다. 감사의말씀본연구는보건복지부의재원으로한국보건산업진흥원의보건의료기술연구개발사업지원에의하여이루어진것임 ( 과제번호 : HI16C0684). 참고문헌 1) Barlam TF, Cosgrove SE, Abbo LM et al. Implementing an antibiotic stewardship program: Guidelines by the infectious diseases society of America and the society for healthcare epidemiology of America. Clin Infect Dis. 2016;62(10):51-77. 2) Green DL. Selection of an empiric antibiotic regimen for hospital-acquired pneumonia using a unit and culture-type specific antibiogram. J Intensive Care Med. 2005;20(5): 296-301. 3) Ross E. Newman, Erin B et al. Impact of a guideline on management of children hospitalized with community acquired pneumonia. - 398 -
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