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항균제 사용의 이론과 실제 I
경희대학교 의과대학
감염 내과
박기호
항균제의 역사: 경험의 시대
2500년 전 중국: 곰팡이 핀 두부
히포크라테스: 와인, 몰약, 무기염
20세기 초: 중금속 (비소, 비스무트[bismuth])
을 매독 치료에 사용
Mandell el al. Principles and Practice of Infectious Diseases. 7th. p267-277
항균제의 역사: 과학의 시대
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
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
MSSA
Drug of choice
1
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)
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 (경
증:6 mg/kg/day)
1
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)
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) ►
1
pneumonia, acute otitis media
AM/CB 2:1 ► skin and soft tissue infection,
bite wound, DM foot
Mandell el al. Principles and Practice of Infectious Diseases. 7th. p320
Fluoroquinones
Lung tissue: serum concentration ► 1.6-6 folds
Ciprofloxacin
Levofloxacin
P. aeruginosa
P. aeruginosa
Moxifloxacin
(Anti-pseudomonal FQ) (Anti-pseudomonal FQ)
S. pneumoniae
S. pneumoniae
(Anti-pneumococal FQ) (Anti-pneumococal FQ)
(Respiratory 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)
Ceftazidime
– Activity against P. aeruginosa
– No activity against CRPA, VRE colonization1
– Less active against almost other bacteria (S. aureus,
streptococcus, E. coli, K. pneumoniae)
Cefepime
– Activity against P. aeruginosa
– 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
ESBL producing E.
ESBL producing E.
coli, K. pneumoniae
coli, K. pneumoniae
Enterococci and
Actinomyces
Seiziure ↑
Seiziure ↓
Ertapenem
Once daily
↓ ESBL producing E.
coli, K. pneumoniae
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
“Less Frequent
Dosing”
Pseudomonas
aeruginosa
→ May be less efficient
→ Be cautious for severe infections
ESBL producing organisms
Ceftazidime (항균 범위 좁다)
Cefepime (neurotoxicity),
Piperacillin/tazobactam
Imipenem (3), meropenem (3),
“Ertapenem↓ (e.g. UTI) (1)”
Pandrug-resistant A. baumannii
Colistin (CSM), Tigeycline
Pandrug-resistant P. aeruginosa
Colistin (CSM)
Colistin vs. Colistin Methanesulfonate (CMS)
Li , et al. Lancet Infect Dis 2006;6:589-601
Colistin vs. Colistin Methanesulfonate (CMS)
Renal tubular secretion !!
Half life
CMS (124  52 min)
vs
Colistin (251  79 min)*
Renal tubular reabsorption !!
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
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
“Respiratory Failure”
ESBL producing organisms
Pandrug-resistant A. baumannii
Pandrug-resistant P. aeruginosa
Imipenem, meropenem,
Ertapenem↓ (e.g. UTI)
Colistin (CSM), Tigeycline
1
Colistin (CSM)
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 사용
하여야 한다.
5. 감염성 설사 의심되는 환자는 metronidazole을 함께 사용하여
야 한다.
Harrison’s Principles of Internal medicine, 18e. Chapter 164
Antibiotics for anaerobic Infections
Category 1
Category 2
Category 3
Category 4
(<2% Resistance)
(<15% Resistance)
(Variable Resistance)
(Resistance)
Carbapenem
Tigecycline
1
“Clindamycin”
Aminoglycosides
Penicillin
Aztreonam
Cephalosporin
TMP/SMX
Metronidazole
β-lactam/β-lactam
inhibitor
High-dose
piperacillin
High-dose ticarcillin
Vancomycin
Erythromycin
Moxifloxacin
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
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 사용
하여야 한다 (X).
5. 감염성 설사 의심되는 환자는 metronidazole을 함께 사용하여
야 한다 (X).
Harrison’s Principles of Internal medicine, 18e. Chapter 164
감염 부위에 대한 고려
Osteoarticular infections
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
1
Voriconazole
(PO)
Moxifloxacin
Nafcillin
Tigecycline
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%)
“Well-tolerable”
→ Poor bioavailability
→ Less efficient
– 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
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
Q&A
Thank you for your kind attention!!