INVITED REVIEW online ML Comm J Neurocrit Care 2009;2 Suppl 1:S16-S21 ISSN 2005-0348 신경계중환자실에서의감염증의진단및적절한항생제의선택 한림대학교의과대학강남성심병원감염내과학교실 이재갑 Systemic Infection in NICU: Management Principle and Proper Choice of Antibiotics Jacob Lee, MD Divisoin of Infectious Disease, College of Medicine, Hallym University Sacred Heart Hospital, Seoul, Korea In neurologic intensive care unit, the management of newly onset fever are very difficult. Because many patients have intravascular devices, urinary catheter, and applying ventilator, health-care associated bacteremia, urinary treac infection, and hospital acquired pneumonia are frequently developed and then morbidity and mortality are also increased. Therefore, rational approach of hospital acquired infection and proper antibiotic choices are very important. J Neurocrit Care 2009;2 Suppl 1:S16-S21 KEY WORDS: Herpes zoster oticus Facial paralysis Hearing loss Puretone audiogram. 서 론 본 론 중환자실환자에서인공호흡기의사용, 중심정맥관, 도뇨관등의여러카테터의유치, 장기간항생제사용등에의하여병원관련감염 (Health care associated infection) 이빈번하게발생하게된다. 게다가신경계중환자실환자들은의식이명료하지않아환자의병력청취및증상의변화를확인하기어렵기때문에발열및감염의원인을찾기가쉽지않다. 또한각병원중환자실마다호발하는병원관련감염의종류도다르며, 원인균도다르고, 항생제감수성양상도다르게나타나기때문에일반적인치료지침을참조하여야하지만, 개별병원의상황에따라변형된항생제사용원칙을가지고있어야한다. 신경계중환자환자에서의발열시의일반적인진단적인접근및호발하는병원관련감염의진단및치료, 각병원의상황에맞는적절한항생제의선택에대해기술하고자한다. Address for correspondence: Jacob Lee, MD Divisoin of Infectious Disease, College of Medicine, Hallym University Sacred Heart Hospital, 948-1 Daerim-dong, Yeongdeungpo-gu, Seoul 150-950, Korea Tel: +82-2-829-5106 E-mail: litjacob@hallym.or.kr 발열환자의일반적인접근실제로발열이있는가? 발열의기준으로심부온도 (core temperature) 가섭씨 38도이상으로정의하기도하며, 38.3도이상으로정의하기도한다. 심부온도의정확한측정은폐동맥카테터등을이용하여측정해야하기때문에실제적으로적용하기어려워심부온도와유사한부위를찾아체온을측정하게되는데, 최근에는적외선을이용한귀체온계나경구체온계를통해측정한다. 액와체온은부정확해서추천하지않는다. 신경계중환자실환자의경우열중추의이상이있거나열중추에영향을주는약물을사용하는경우가많으며, 그외에도동반된내과적문제로인하여투석, 항온매트리스, 온열전구, 체외순환등을치료법을빈번하게사용하기때문에측정되는체온이심부온도를반영하지못할수있다. 1 적절한세균배양은어떻게할것인가? 신경계중환자실환자의경우증상을잘말하지않기때문에발열이있을경우적절한배양결과가환자의감염의 S16 Copyright c 2009 The Korean Neurocritical Care Society
Systemic Infection in NICU: Management Principle and Proper Choice of Antibiotics J Lee 실마리를제공하는경우가많다. 특히혈액배양은매우중요하며적절한방법으로시행되어야한다. 배양검사는새로운발열이있었을때항생제투여전내지는항생제의변경전에반드시시행되어야하며, 이전에는 30분간격으로 3회의채혈을권장하였으나, 최근에는다른부위에서의 2회채혈만으로적절한혈액배양결과를얻을수있다는보고가있다. 혈액배양과함께감염의의심이되는부위의배양 ( 객담, 소변, 창상등 ) 도동시에실시되어야한다. 1 병원관련감염의진단및치료이장에서는병원획득폐렴 (hospital acquired pneumonia), 카테터관련균혈증 (catheter related bacteremia), 카테터관련요로감염 (catheter associated urinary tract infection) 등에대하여진단적접근및최신치료경향을소개하고자한다. 병원획득폐렴병원획득폐렴은중환자실감염의약 25% 를차지하며, 인공호흡기관련폐렴 (ventilator-associated pneumonia) 은기도삽관을한환자의 9~27% 에서발생한다. 인공호흡기관련폐렴은주로기도삽관후 4일째까지가장빈번하게발생하며, 이는기도삽관시술자체가폐렴의유발인자이기때문이다. 급성뇌경색환자에서의병원획득폐렴의위험인자는 65세이상, 말더듬증 (dysarthria) 또는언어상실증 (aphagia) 이동반된경우, modified Rankin Sale이 4점이상, Abbreviated Mental Test가 8점미만, 수분연하검사 (water swallow test) 의실패등이었다. 2 정의병원획득성폐렴은입원후 48시간이후에발생한폐렴을말하며, 4일이내에발생할경우조기병원획득성폐렴, 5일이후에발생한경우를후기병원획득성폐렴으로정의한다. 이러한시기상의구분은조기병원획득성폐렴은지역사회내에서획득된세균에의한감염이많고, 후기병원획득성폐렴은병원또는중환자실에서획득된세균에의한감염이많기때문이다. 인공호흡기관련폐렴은기도삽관후 48~72 시간이후에발생한폐렴으로정의하며기도삽관시점을기준으로조기와후기폐렴으로분류한다. 3,4 진단흉부엑스선검사상새로이발생했거나, 진행하는새로운 음영이발생한경우에의심을하며, 동반되는발열과백혈구증가, 화농성의가래및객담배양결과의양성소견을보이는경우에진단이된다. 객담의배양은항생제사용에있어무척중요하다. 상기도의상재균내지는오염균을배제하고하기도의실제폐렴의원인균을분리하기위해서사용되는방법들은경기관흡인의정량배양 (protected specimen brush: PSB), 기관지내시경을이용한폐포세척술 (Brochoalveolar lavage: BAL) 등의방법이있다. 이러한객담배양은항생제투여전내지는변경전에시행되어야한다. 3 치료객담배양결과전까지경험적항생제를사용을위해고려할부분은폐렴의발생시기즉조기 (4일이내 ) 인지후기 (5일이후 ) 인지, 또한다제내성세균이분리될수있는위험인자가있는지에대한것이다. 지금까지밝혀진다제내성균의위험인자는 90이내의항생제사용력, 5일이상의현입원력, 지역사회또는중환자실내에서의다제내성균의호발, 면역저하자등이다. 이러한폐렴의발생시기및다제내성균의위험인자의보유여부에따라 2005 년미국흉부학회 (American Thoracic Society: ATS) 및감염학회 (Infectious Disease Society of America: IDSA) 는공동치료지침을발표하였으며, 2007년에는한국을비롯한아시아 10개국이참여한 Asian HAP Working Group에서중환자실내 (Methicillin-resistant Staphlococcus aureus: MRSA), 광범위내성 Pseudomonas 및 Acineotbacter의분리율이높은아시아지역의특성을반영한치료지침을발표하였다 (Table 1-4). 3,4 이러한치료지침을바탕으로각중환자실에서주로유행하는원인균및내성현황에따라적절한조합을선택하거나변형하여적용하여야한다. 치료의평가및치료기간치료의평가는항생제사용후 48시간에서 72시간내에실시한다. 객담배양을통해원인균이확인되었고, 임상적으로호전시에는감수성결과에따라서항생제를선택적항생제로조정한다 (de-escalating therapy). 5 감수성결과와일치하지않을경우에는감수성결과와일치하는항생제로변경한다. 배양음성인경우에는진단이틀렸거나, 폐농양, 농흉등의폐렴의합병증동반여부를확인하여원인질환에따른항생제의조정또는추가적인수술적조치가필요할수있다. 장기간항생제사용에도배양음성이거나치료에반응하지않을경우에는바이러스성폐렴이나, 진균성폐 S17
J Neurocrit Care 2009;2 Suppl 1:S16-S21 TABLE 1. Initial empirical antibiotics treatment for earlyt HAP in patients with no risk factors for multidrug-resistant pathogen: Derived from guidelines for management of HAP/VAP from ATS/IDSA and Asian HAP Working Group Potential pathogen ATS/IDSA Asian HAP working group Streptococcus pneumonia Ceftrixone Ceftrixone,cefotaxime Hemophilus influenza Methicillin-sensitive Levofloxacin, moxifloxacin, Moxifloxacin, levofloxacin Staphylococcus aureus Ciprofloxacin Antibiotic-sensitive enteric Amoxicillin.clavulanic acid, Gram-negative bacilli Ampicillin/sulbactam Ampicillin.sulbactam Escherichia coli Klebsiella pneumonia Ertapenem Ertapenem Enterobacter species Proteus species Serratia marcescens 3 rd -generation cephalosporin macrolide Monobactam plus clidamycin (for β-lactam-allegic patients) TABLE 2. Initial empirical antibiotics treatment for late-onset HAP in patients with risk factors for multidrug-resistant pathogen: Derived from guidelines for management of HAP/VAP from ATS/IDSA and Asian HAP Working Group Potential pathogen ATS/IDSA Asian HAP Working Group Pathogen listed in Table 1 abd MDR pathogen Antipseudomonal cephalosporin (cefepime, ceftazidime) Antipseudomonal cephalosporin (cefepime, ceftazidime) Pseudomona aeruginosa Klebsiella pneumonia (ESBL+) Antipseudomonal carbapenem (imipenem or meropenem) Antipseudomonal carbapenem (imipenem or meropenem) Acintobacter species Antipseudomonal β-lactam/β-lactamase inhibitor (piperacillin/tazobactam) +/- Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) Aminoglycoside (amikacin, gentamycin, or tobramycin) β-lactam/β-lactamase inhibitor (piperacillin/tazobactam) fluoroquinolone (ciprofloxacin or levofloxacin) Aminoglycoside (amikacin, gentamycin, or tobramycin) Cefoperazole.sulbactam plus fluoroquinolone or aminoglycosides plus ampicillin/sulbactam Fluoroquinolone (ciprofloxacin) plus aminoglycoside MRSA Linezolid or vancomycin Linezolid or vancomycin Legionella pneumophilla Azithromycin or fluoroquinolone 렴도고려하여야한다. 3,4 일반적인병원획득폐렴의경우치료기간은 7~8일을권장하고있으며, Pseudomonas aeruginosa의경우세균학적제균이쉽지않으므로, 14~21 일의투여기간이권장되고있다. 최근문제가되고있는광범위내성세균들 (Pseudomonas aeruginosa, Acinetobacter 균주, ESBL양성그람음성균 ) 의경우에는대체로 14일정도의치료기간을추천하고있다. 4 카테터관련균혈증중환자실의환자는수액또는영양공급, 중심정맥압측정등을위해중심정맥관을가지게된다. 중심정맥관은환자의상태유지에필수적이긴하나, 여러세균의출입소로작용할수있다. 미국에서는 1,000 카테터일 (catheter day) 마다 2~5건의카테터관련균혈증이발생하여, 이로인하여약 2,000~20,000 여명의환자가사망하고있다. 6 또한미국공공의료보험에서는카테터관련균혈증에대해서는 S18
Systemic Infection in NICU: Management Principle and Proper Choice of Antibiotics J Lee TABLE 3. Initial empirical antibiotics treatment for early-onset VAP: Derived from guidelines for management of HAP/VAP from ATS/IDSA and Asian HAP Working Group Potential pathogen ATS/IDSA Asian HAP Working Group Pathogen listed in Table 1 abd MDR pathogen Ceftrixone Pseudomona aeruginosa Antipseudomonal cephalosporin (cefepime) Klebsiella pneumonia (ESBL+) Levofloxacin, moxifloxacin, ciprofloxacin Antipseudomonal carbapenem (imipenem or meropenem) Acintobacter species MRSA Ampicillin/sulbactam β-lactam/β-lactamase inhibitor (piperacillin/tazobactam) +/- Ertapenem Fluoroquinolone (ciprofloxacin or levofloxacin) Aminoglycoside (amikacin, gentamycin, or tobramycin) Linezolid or vancomycin TABLE 4. Initial empirical antibiotics treatment for early-onset VAP: Derived from guidelines for management of HAP/VAP from ATS/IDSA and Asian HAP Working Group Potential pathogen ATS/IDSA Asian HAP Working Group Pathogen listed in Table 1 abd MDR pathogen Antipseudomonal cephalosporin (cefepime, ceftazidime) Antipseudomonal cephalosporin (cefepime, ceftazidime) Pseudomona aeruginosa Klebsiella pneumonia (ESBL+) Antipseudomonal carbapenem (imipenem or meropenem) Antipseudomonal carbapenem (imipenem or meropenem) Acintobacter species Antipseudomonal β-lactam/β-lactamase inhibitor (piperacillin/tazobactam) plus +/- Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) Aminoglycoside (amikacin, gentamycin, or Tobramycin) β-lactam/β-lactamase inhibitor (piperacillin/tazobactam) Fluoroquinolone (ciprofloxacin or levofloxacin) Aminoglycoside (amikacin, gentamycin, or tobramycin) Cefoperazole.sulbactam plus fluoroquinolone or aminoglycosides plus ampicillin/sulbactam Fluoroquinolone (ciprofloxacin) plus aminoglycoside MRSA Linezolid or vancomycin Linezolid or vancomycin 모든책임을의사의과실로간주하여 2008년부터보험급여를중지하는법안을통과시킨바있다. 진단중심정맥관을가진환자에서다른감염으로설명되지않는갑작스러운발열이발생하였을경우에제일먼저카테터관련균혈증을생각해야한다. 진단은카테터를통해채혈된혈액및말초정맥에서채혈된혈액에서동일한균주가배양되거나, 카테터말단정량배양결과에서 10 2 CFU 이상배양되면서, 말초정맥에서 동일균주가배양되는경우에확진된다. 6 감염이의심되지않는경우에는매카테터제거시마다말단배양검사를시행하는것은권고하지않고있다. 대개의카테터관련균혈증의흔한원인균은 coagulase negative Staphylococci, Staphylococcus aureus, Enterococcus, 그람음성간균, candida 균주등이다. 치료카테터관련균혈증이의심시카테터의제거가가장선행되어야한다. 경험적항생제치료는국내중환자실의 MRSA S19
J Neurocrit Care 2009;2 Suppl 1:S16-S21 의분리율이높기때문에 vancomycin 사용을고려하여야하며, Pseudomaonas를포함한그람음성균에의한균혈증을배제할수없는경우에는 ceftazidime 또는 cefepime 의추가사용을고려하여야한다. 또한중증감염, 장기적으로항생제사용중인환자, 면역억제치료를받고있거나면역저하질환을가진환자의경우에는진균에의한균혈증을염두에두어야하며, 환자의상태에따라 amphotericine B 또는 fluconazole 의사용을고려할수있다. 최근많은대학병원의진단검사의학과에서는균혈증이있는경우그람양성균내지는그람음성균또는진균이배양되는지일차결과를 2~3일내에보고하고있으므로, 이결과에따라경험적항생제를조정하고, 추후 1~2일내에보고되는최종배양결과에따라선택적항생제를결정하면광범위항생제의복합사용기간을최소화할수있다. 예방카테터삽입시부터철저한손위생, 수술모자, 수술가운, 장갑을착용하도록권장 (maximal barrier precaution: MBP) 하고있으며, 이러한주의조치만으로도카테터관련감염을절반이하로줄일수있고비용효과적이라는국내외보고가있다. 7 삽입부위는쇄골하정맥부위가가장감염위험이낮으며, 경정맥이나대퇴정맥의경우는감염의위험이높아응급상황이아니고서는추천하지않는다. 경정맥이나대퇴정맥부위에삽입한중심정맥관은되도록삽입 48시간이내에제거하도록하고있다. 삽입후에는매일카테터삽입부위를확인하여발적여부, 배농여부를확인하여삽입부위감염을최소화하여야한다. 카테터의유지기간은환자의상태가안정되는대로최소화하여야한다. 카테터관련요로감염신경계중환자실환자들은의식저하, 신경인성방광등의이유로장기적인도뇨관삽입을하게된다. 도뇨관을삽입한환자에서매일 3~10% 씩세균뇨가발생하며, 2주후에는거의 90% 의환자에서세균또는진균뇨가발생한다. 8 세균뇨가있는대부분의환자에서는발열이나요로계감염의증상이발생하지않기때문에, 항생제사용은발열이나백혈구증가등의임상적증상이있을경우에제한하여사용하여야한다. 9 다만비뇨기과적침습적처치나수술, 항암치료등에의한백혈구감소환자에서는균혈증이동반될수있으므로, 환자의상태에따라시술직전에적절한항생제치료가필요할수있다. 진단미국질병관리센터 (CDC) 는소변배양검사에서양성인환자에서 (10 4 CFU 이상 ) 37.8 도이상의발열, 긴박뇨, 빈뇨, 배뇨통, 치골부위압통, 의식저하, 혈압저하증한가지이상의증상이있을경우요로감염으로정의하였다. 8 이러한정의가카테터유치환자에서는적용하기어렵기때문에미국공중보건학회 (Society for Healthcare Epidemiology of America) 에서는소변배양양성이면서 37.9도이상의발열, 갈비척추부위의압통 (tenderness of costovertebral angle: CVA tenderness), 경직 (rigor) 또는새로이발생한섬망증상이생겼을경우에카테터관련요로감염으로정의하여치료하도록하였다. 8 치료도뇨관삽입초기에는 E. coli 등의장내그람음성세균들이주된감염을일으키지만, 카테터삽입의기간이길어질수록 ESBL 양성균또는 Pseudomonas 등의다제내성세균에의한감염이증가하며, 장기적인항생제사용이선행되었을경우에는진균에의한요로감염도발생할수있으므로, 경험적항생제선택에있어서시기별고려가필요하다. 경험적항생제로 3세대 cephalosporin 을추천하고있으나환자가최근에항생제노출력이있거나, 중환자실내에서 ESBL양성균이나 Pseudomonas 감염이호발하는경우에는초기부터 carbapenem내지는항 Pseudomonas 효과가있는 β-lactam/β-lacctam억제제 (piperacillin/tazobactam) 의사용을고려하여야한다. 8 진균뇨에의한진균혈증이의심되는경우는 fluconazole 또는 amphotericine- B의사용을고려하여야한다. 배양결과의확인후에는선택적항생제로조정하도록한다. 결 론 신경계중환자실내감염증에서의항생제의선택은개별중환자실마다의특성, 환자개개인의면역상태및기저질환여부, 가용가능한진단적도구등에따라서달라질수있다. 기본적인치료지침을병원사정에맞게조정하여사용하여야하며, 이를위해서는임상과와진료지원부서인감염내과, 진단검사의학과, 영상의학과간의협조가매우중요하다. REFERENCES 1. Naomi PG, Philip SB, John GB, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases S20
Systemic Infection in NICU: Management Principle and Proper Choice of Antibiotics J Lee Society of America, Crit Care Med 2008;36:1330-49. 2. Cameron S, Lynsey B, Jeremy B. Risk Factors for Chest Infection in Acute Stroke: A Prospective Cohort Study, Stroke 2007;38:2284-91. 3. American thoracic society Board of director and Infectious disease society of America Guidline Committee, Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pnejmonia, Am J Respri Crit Care Med 2005;171:388-416. 4. Jae-Hoon Song and the Asian HAP Working Group, Treatment recommendations of hospital-acquired pneumonia in asian countries: first consensus report by the Asian HAP Working Group, Am J Infect Control 2007;36:supplement 2. 5. Joseph LK, Eric S, Marc P, et al. Tackling empirical antibiotic therapy for ventilator-associated pneumonia in your ICU: Guidance for implementing the guidelines, Semin Respir Crit Care Med 2009;30:102-15. 6. Leonard AM, Barry MF, Robert JS, et al. Guidelines for the Management of Intravascular Catheter-Related Infections, CID 2001;32:1249-72. 7. Kent KH, David LV, Benjamin AL, et al. Use of Maximal Sterile Barriers during Central Venous Catheter Insertion: Clinical and Economic Outcomes, CID 2004;39:1441-5. 8. Peter T, Bela K, Truls EB, et al. European and Asian guidelines on management and prevention of catheter-associated urinary tract infections, International J Antimicrobial Agents 2008;31:s68-78. 9. Matthew C, Manuel EC, Richard MC, et al. Inappropriate Treatment of Catheter-Associated Asymptomatic Bacteriuria in a Tertiary Care Hospital, CID 2009;48:1182-8. S21