항균제 사용의 이론과 실제 I 경희대학교 의과대학 감염 내과 박 기 호

항균제의 역사: 경험의 시대 2500년 전 중국: 곰팡이 핀 두부 히포크라테스: 와인, 몰약, 무기염 20세기 초: 중금속 (비소, 비스무트[bismuth])을 매독 치료에 사용 김탁: 1) 김성한: 1) 박성연: 1) 문송미: 1) 정용필: 2) 나) 최성호: 2) 가), 나) 이미숙: 2) 가), 나) 손준성: 2) 가), 나) 조오현: 2) 가), 다) 이유미: 2) 가), 다) 박기호: 2) 가), 나), 다) 전민혁: 2) 가), 나) 최상호: 3) 1) 6개월 치료한다 (4/17) 2) 상황에 따라 6개월 치료를 연장한다 (8/17) 가) 치료 종료할 때 림프절 크기가 큰 경우 (7/17) 나) 치료 중 역설적 반응이 있었던 경우 (6/17) 다) 환자가 재발에 대하여 불안해 하는 경우 (3/17) 3) 보통 6개월보다 길게 치료한다 (9개월) (4/17) Mandell el al. Principles and Practice of Infectious Diseases. 7th. p267-277

항균제의 역사: 과학의 시대 1928년: 플레밍 푸른 곰팡이(Penicillium)의 항균 효과 김탁: 1) 김성한: 1) 박성연: 1) 문송미: 1) 정용필: 2) 나) 최성호: 2) 가), 나) 이미숙: 2) 가), 나) 손준성: 2) 가), 나) 조오현: 2) 가), 다) 이유미: 2) 가), 다) 박기호: 2) 가), 나), 다) 전민혁: 2) 가), 나) 최상호: 3) 1) 6개월 치료한다 (4/17) 2) 상황에 따라 6개월 치료를 연장한다 (8/17) 가) 치료 종료할 때 림프절 크기가 큰 경우 (7/17) 나) 치료 중 역설적 반응이 있었던 경우 (6/17) 다) 환자가 재발에 대하여 불안해 하는 경우 (3/17) 3) 보통 6개월보다 길게 치료한다 (9개월) (4/17) 1928년: 플레밍 푸른 곰팡이(Penicillium)의 항균 효과 1941년: 포도상구균 감염 환자에서 첫 투여 Mandell el al. Principles and Practice of Infectious Diseases. 7th. p267-277

Appropriate antibiotic therapy Virulence Organism Site of Infection Host Drug Interactions Oral antibiotic therapy

병독성에 대한 고려

병독성과 오염균 CoNS, Bacillus, Corynacterium: prosthetic device infection (c-line)이 아니면 오염이 많음 Gram (+) rods Weinstein et al. Clin Infect Dis 1997; 24:584-602

Gram-negative bacteremia는 fungemia (yeast)는 거의 오염이 없다. 병독성과 오염균 Gram-negative bacteremia는 fungemia (yeast)는 거의 오염이 없다. Weinstein et al. Clin Infect Dis 1997; 24:584-602

병독성과 오염균 0d Weinstein et al. Clin Infect Dis 1997; 24:584-602

원인균에 대한 고려

원인균에 대한 고려 Organisms Drug of choice MSSA Nafcillin ≥ cefazolin MRSA Vancomycin (30 mg/kg/day) ≥ Teicoplanin (6~12 mg/kg/day) Streptococcus spp. (viridians streptococci, S. agalactiae, Enterococcus spp., etc.) PCN S. pneumoniae PCN, FQ (for pneumonia) Enterobacteriaceae (E. coli, Klebsiella, other) 3rd generation CS, FQ Pseudomonas aeruginosa Ceftazidime, Cefepime, Piperacillin/tazobactam ESBL producing organisms Imipenem, meropenem, Ertapenem Pandrug-resistant A. baumannii Colistin (CSM), Tigeycline Pandrug-resistant P. aeruginosa Colistin (CSM)

Cefazolin (vs. nafcillin) for MSSA On the occasion of a meeting, LA, California, during the question-and-answer session. Dr. Marvin Turck, “That’s drug for my mother-in law but not for my mother !!” Editor’s forum: drugs for your mother-in law. Infect Dis Clin Pract 1992;1:46-7 Fernandez-Guerrero ML, et al. 2005; 41:127

원인균에 대한 고려 Organisms Drug of choice MSSA Nafcillin (중증) ≥ cefazolin MRSA Vancomycin (30 mg/kg/day) ≥ Teicoplanin (6~12 mg/kg/day) Streptococcus spp. (viridians streptococci, S. agalactiae, Enterococcus spp., etc.) PCN S. pneumoniae PCN, FQ Enterobacteriaceae (E. coli, Klebsiella, other) 3rd generation CS, FQ Pseudomonas aeruginosa Ceftazidime, Cefepime, Piperacillin/tazobactam ESBL producing organisms Imipenem, meropenem, Ertapenem Pandrug-resistant A. baumannii Colistin (CSM), Tigeycline Pandrug-resistant P. aeruginosa Colistin (CSM) 1

Teicoplanin (vs. vancomycin) for MRSA Approved in Europe, but not approved in US Strength Once daily (6 mg~12 mg/kg/day) Less frequent ADR (nephrotoxicity, skin rash, and allergic drug reaction) Limitation More treatment failure (6 mg/kg/day, 10 mg/kg/day) Trough concentration: not available Recommendation 12 mg/kg/day or more for endocarditis, osteoarticular infections Tapering regimen Mandell et al. Clin Infect Dis 2007; 44 Suppl 2:S27-72.

원인균에 대한 고려 Organisms Drug of choice MSSA Nafcillin (중증) ≥ cefazolin MRSA Vancomycin (중증: 30 mg/kg/day) ≥ Teicoplanin (경증:6 mg/kg/day) Streptococcus spp. (viridians streptococci, S. agalactiae, Enterococcus spp., etc.) PCN S. pneumoniae PCN, FQ Enterobacteriaceae (E. coli, Klebsiella, other) 3rd generation CS, FQ Pseudomonas aeruginosa Ceftazidime, Cefepime, Piperacillin/tazobactam ESBL producing organisms Imipenem, meropenem, Ertapenem Pandrug-resistant A. baumannii Colistin (CSM), Tigeycline Pandrug-resistant P. aeruginosa Colistin (CSM) 1

Amoxicillin/clavulanate (AM/CB) Tablets 250 mg/125 mg (2:1), 500 mg/125 mg (4:1), 875 mg/125 mg (7:1), 1000 mg/62.5 mg (16:1) AM/CB (vs. amoxicillin): actibacterial coverage↑ : MSSA, MS-CoNS, H. infuenzae, M. catarrhalis, E. coli, K. pneumoniae Activity against S. pneuomiae: depends on dose of amoxicillin !! Mandell et al. Clin Infect Dis 2007; 44 Suppl 2:S27-72.

Amoxicillin/clavulanate (AM/CB) Mandell et al. Clin Infect Dis 2007; 44 Suppl 2:S27-72.

Amoxicillin/clavulanate (AM/CB) AM/CB 250 mg/125 mg (2:1) for pneumonia: “12T (3 g/1.5 gm)” less tolerable, clavulanate ADR (N/V, diarrhea) AM/CB (4:1, 7:1, 16:1, S. pneumoniae) ► pneumonia, acute otitis media AM/CB 2:1 ► skin and soft tissue infection, bite wound, DM foot 1 Mandell el al. Principles and Practice of Infectious Diseases. 7th. p320

Fluoroquinones Lung tissue: serum concentration ► 1.6-6 folds Ciprofloxacin Levofloxacin Moxifloxacin P. aeruginosa (Anti-pseudomonal FQ) S. pneumoniae (Anti-pneumococal FQ) (Respiratory FQ) Anaerobe (C. difficile colitis) M. Tuberculosis M. tuberculosis Mandell el al. Principles and Practice of Infectious Diseases. 7th. p493

원인균에 대한 고려 Organisms Drug of choice MSSA Nafcillin (중증) ≥ cefazolin MRSA Vancomycin (30 mg/kg/day) ≥ Teicoplanin (6~12 mg/kg/day) Streptococcus spp. (viridians streptococci, S. agalactiae, Enterococcus spp., etc.) PCN S. pneumoniae PCN (high dose, AM/CB >2:1), FQ (Levo, Moxi) for pneumonia Enterobacteriaceae (E. coli, Klebsiella, other) 3rd generation CS, FQ Pseudomonas aeruginosa Ceftazidime, Cefepime, Piperacillin/tazobactam ESBL producing organisms Imipenem, meropenem, Ertapenem Pandrug-resistant A. baumannii Colistin (CSM), Tigeycline Pandrug-resistant P. aeruginosa Colistin (CSM)

Ceftazidime and cefepime (vs. ceftriaxone) Activity against P. aeruginosa No activity against CRPA, VRE colonization1 Less active against almost other bacteria (S. aureus, streptococcus, E. coli, K. pneumoniae) Cefepime Equally or more active against other bacteria (S. aureus, streptococcus, E. coli, K. pneumoniae) ADR: seizure, encephalopathy!! 1Livornese et al. Ann Intern Med 1992; 117:112-6

Carbapenem Imipenem Meropenem Ertapenem ESBL producing E. coli, K. pneumoniae Once daily Enterococci and Actinomyces Seiziure ↓ ↓ ESBL producing E. coli, K. pneumoniae Seiziure ↑ No activity against P. aeruginosa Mandell el al. Principles and Practice of Infectious Diseases. 7th. p493

원인균에 대한 고려 Organisms Drug of choice MSSA Nafcillin (6) ≥ “cefazolin (3)” MRSA Vancomycin (30 mg/kg/day) (2) ≥ “Teicoplanin (6mg/kg/day) (1)” Streptococcus spp. (viridians streptococci, S. agalactiae, Enterococcus spp., etc.) PCN S. pneumoniae PCN (high dose, AM/CB >2:1), FQ (Levo, Moxi) for pneumonia Enterobacteriaceae (E. coli, Klebsiella, other) 3rd generation CS, FQ Pseudomonas aeruginosa Ceftazidime (항균 범위 좁다) Cefepime (neurotoxicity), Piperacillin/tazobactam ESBL producing organisms Imipenem (3), meropenem (3), “Ertapenem↓ (e.g. UTI) (1)” Pandrug-resistant A. baumannii Colistin (CSM), Tigeycline Pandrug-resistant P. aeruginosa Colistin (CSM) “Less Frequent Dosing” → May be less efficient → Be cautious for severe infections

Colistin vs. Colistin Methanesulfonate (CMS) Li , et al. Lancet Infect Dis 2006;6:589-601

Colistin vs. Colistin Methanesulfonate (CMS) Renal tubular secretion !! Renal tubular reabsorption !! CMS (124  52 min) vs Colistin (251  79 min)* Half life Nephrotoxicity Neurotoxicity (neuromuscular block) → “Respiratory Failure” Li, et al. J Antimicrob Chemother 2003;52:987-992

Colistin Methanesulfonate (CMS) toxicity After 5 days of IV CMS, rapidly progressive weakness with dyspnea, tachypea and severe extremity pain After 3 day of inhaled CMS, CO2 retention Wahby, et al. Clin Infect Dis 2010;50(6):e38-40

“Respiratory Failure” 원인균에 대한 고려 Organisms Drug of choice MSSA Nafcillin (중증) ≥ cefazolin MRSA Vancomycin (30 mg/kg/day) ≥ Teicoplanin (6~12 mg/kg/day) Streptococcus spp. (viridians streptococci, S. agalactiae, Enterococcus spp., etc.) PCN S. pneumoniae PCN (high dose, AM/CB >2:1), FQ (Levo, Moxi) for pneumonia Enterobacteriaceae (E. coli, Klebsiella, other) 3rd generation CS, FQ Pseudomonas aeruginosa Ceftazidime (항균 범위 좁다) Cefepime (neutoxiciy), Piperacillin/tazobactam ESBL producing organisms Imipenem, meropenem, Ertapenem↓ (e.g. UTI) Pandrug-resistant A. baumannii Colistin (CSM), Tigeycline Pandrug-resistant P. aeruginosa Colistin (CSM) “Respiratory Failure” 1

Quiz: anaerobic Infections 1. 혐기성 감염이 의심되는 경우, diaphragm 위는 clindamycin, diaphragm 아래는 metronidazole을 사용한다. 2. 농이 있는 환자는 혐기성 균에 대한 항균제를 사용하여야 한다. 3. 심한 냄새가 나는 경우, 혐기성 감염에 진단적이다. 4. 흡입성 폐렴 의심되는 환자는 혐기성 균에 대한 항균제를 사용하여야 한다. 5. 감염성 설사 의심되는 환자는 metronidazole을 함께 사용하여야 한다. Harrison’s Principles of Internal medicine, 18e. Chapter 164

Antibiotics for anaerobic Infections Category 1 (<2% Resistance) Category 2 (<15% Resistance) Category 3 (Variable Resistance) Category 4 (Resistance) Carbapenem Tigecycline “Clindamycin” Aminoglycosides Metronidazole High-dose piperacillin Penicillin Aztreonam β-lactam/β-lactam inhibitor High-dose ticarcillin Cephalosporin TMP/SMX Vancomycin Erythromycin Moxifloxacin 1 Harrison’s Principles of Internal medicine, 18e. Chapter 164

Chapter 164. Infections due to mixed anaerobic organisms Abscess: (1) aerobic infections (e.g. K. pneumoniae liver abscess, S. aureus psoas abscess) (2) aerobic and anaerobic infections (e.g. secondary peritonitis) Although a putrid-smelling discharge is considered diagnostic for anaerobic infection, it usually develops late in the course Pneumonia: almost due to micro-aspiration Harrison’s Principles of Internal medicine, 18e. Chapter 164

국내 감염성 설사의 주 원인균 KCDC. Public Health Wkly Rep 2010;3:428-32

Stool Multiplex PCR 바이러스 5종 → 18.5% (75/405), 세균 8종 → 24.4% (99/405) 바이러스, 세균 13종 → 34.1% (138/405) Lee S, et al. Ann Clin Microbiol 2013; 16:33-8

Noninflammatory Diarrhea Inflammatory Diarrhea (invasion or cytotoxin) 감염성 설사의 분류 Noninflammatory Diarrhea (enterotoxin) Inflammatory Diarrhea (invasion or cytotoxin) Proximal small bowel Colon or distal small bowel Watery diarrhea Dysentery or Bloody diarrhea No fecal leukocyote Mild to no increase in fecal lactoferrin Fecal polymorhonuclear leukocytes Substantial increase in fecal lactoferrin Vibrio cholerae Enterotoxic E. coli Enteroaggregative E. coli Clostridium perfringens Bacillus cereus Staphylococcus aureus Aeromonas hydrophila Plesiomonas shigelloides Rotavirus, norovirus, enteric adenoviruses Giardia lamblia Cryptosporidium spp. Cyclospora spp. Microsporidia Shigella spp. Salmonella spp. Campylobacter jejuni Enterohemorrhagic E. coli (STEC) Enteroinvasive E. coli Yersinia enterocolitica Listeria monocytogenes Vibrio parahaemolyticus Clostridium difficile A. hydrophilia P. Shigelloides Entamoeba histolytica Klebsiella oxytoca Harrison’s Principles of Internal medicine, 18e. Chapter 164

Quiz: anaerobic Infections 1. 혐기성 감염이 의심되는 경우, diaphragm 위는 clindamycin, diaphragm 아래는 metronidazole을 사용한다 (X). 2. 농이 있는 환자는 혐기성 균에 대한 항균제를 사용하여야 한다 (X). 3. 심한 냄새가 나는 경우, 혐기성 감염에 진단적이다 (O). 4. 흡입성 폐렴 의심되는 환자는 혐기성 균에 대한 항균제를 사용하여야 한다 (X). 5. 감염성 설사 의심되는 환자는 metronidazole을 함께 사용하여야 한다 (X). Harrison’s Principles of Internal medicine, 18e. Chapter 164

감염 부위에 대한 고려

Osteoarticular infections 1) S. aureus: levofloxacin 750 mg QD + rifampin 300 mg bid 2) GNB: fluoroquionolone Landersdorfer et al. Clin Pharmacokinet 2009; 48:89-124

CNS penetration Cf. Poor CNS penetration: β-lactam/β-lactam inhibitor CNS drugs/dose Brain abscess Meningitis Eye infection (orbital cellulitis): nafcillin + CTRX + metronidazole Epidural abscess Tunkel et al. Clin Infect Dis 2004; 39:1267-84

환자 요인에 대한 고려

Age Gastric acidity: PO drug absorption Renal function ↓ High dose of PCN, cephalosporin, imipenem : Severe neurotoxic reaction such as myoclonus, seizure, and coma Aminoglycoside: ototoxicity ↑ Fluoroquinolone: cartilage damage and arthropathy in young adults vs. tendinopathy in older adults ADR ↑, hypersensitivity ↑ (previously exposed) Mandell el al. Principles and Practice of Infectious Diseases. 7th. p269

No dosage adjustment with renal insufficiency Antibacterial Antifungals Anti-TBc Azithromycin Anidulfangin Ethionamide Ceftriaxone Caspofungin Isoniazid Doxycycline Micafungin Rifampin Linezolid Voriconazole (PO) Moxifloxacin Nafcillin Tigecycline 1 Sanford Guide. 44th Edition. p219

약물 상호 작용

TMP/SMX TMP/SMX plus ACEi/ARB: hyperkalemia↑ TMP/SMX plus ACEi/ARB (vs. ACEi/ARB) : 7-fold increased risk of hyperkalemia-associated hospitalization Antoniou et al. Arch Intern Med 2010; 170:1045-9

Fluoquoroqinolone Antiarrhythmics (procainamide, amiodarone) → Q-T interval (torsade) ↑ Antacids, vitamins, diary products, sucralfate → Oral absorption of fluoroquinolone ↓ Rifampin → level of fluoroquinolone ↓ Warfarin → PT ↑ NSAIDS → CNS stimulation/seizures !! Sanford Guide. 44th Edition. p225

경구 항균제의 사용

(Oral) Bioavailability The fraction of an administered dose of unchanged drug that reaches the systemic circulation. IV drugs: bioavailability 100% Po drugs: bioavailability generally decreases due to incomplete absorption and first-pass metabolism Bioavailability must be considered when calculating dosages for non-intravenous routes of administration.

(Oral) Bioavailability Good bioavailability Amoxicillin (80%), TMP/SMX (80%) CIP (70%), Levofloxacin (99%), Moxiflxoacin (89%) 1st GCS (90%) (e.g. SSTI, UTI); 2nd GCS: cefaclor (93%), cefoxitin (95%) Poor bioavailability: safe and well-tolerable 2nd GCS: cefuroxime (52%) 3rd GCS: cefdinir (25%), cefditoren (16%), cefixime (50%), cefpodoxime (46%) Cf. Ceftibuten (80%): limited activity against S. pneumoniae and MSSA “Well-tolerable” → Poor bioavailability → Less efficient

Summary 1. Optimal and alternative regimen: Nafcillin ≥ Cefazolin, Vanco ≥ Teico, IMP/MER ≥ Ertapenem 2. Streptococcus spp.: PCN (high dose) 3. Colistin (CMS) → neurotoxicity, respiratory failure 4. Anaerobic infections: mixed, clindamycin↓, aspiration 5. Oral drugs: “Well-tolerable”, “Poor bioavailability”, “Less efficient”, “3rd GS”. 6. Drug interactions: ACE/ARB + TMP/SMX→ hyperkalemia

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