Principles of Antimicrobial Therapy Doo Ryeon Chung, MD, PhD Professor of Medicine, Division of Infectious Diseases Director, Infection Control Office SUNGKYUNKWAN UNIVERSITY SCHOOL OF MEDICINE
CASE 1 F/32 SLE since the age of 21 Medication : 1 week PTA, fever & headache Headache aggravated, diplopia Physical exam. at ER Alert Neck stiffness Bilateral lateral gaze palsy LAB CSF analysis WBC 100 /mm 3 PMN 82% Lympho 5% Glucose 33 mg/dl Protein 41 mg/dl
CASE 1 What will you prescribe for empirical antimicrobial therapy in this patient? 1) Ceftriaxone 2) Ceftriaxone + vancomycin 3) Penicillin G 4) Ampicillin 5) Ceftriaxone + ampicillin + vancomycin
Antimicrobial therapy Empirical therapy Definitive therapy (Pathogen-specific) Prophylactic therapy
Empirical antimicrobial therapy What is the infecting organism? Antimicrobial susceptibility of the infecting organism Host factors
Etiology of bacterial meningitis in Korean adults Moon SY, Chung DR, et al. Eur J Clin Microbiol Infect Dis 2010;29:793
Etiology of bacterial meningitis in Korean adults Moon SY, Chung DR, et al. Eur J Clin Microbiol Infect Dis 2010;29:793
Common underlying diseases or conditions in Listeria meningitis Old age Immunocompromised hosts
Etiology of bacterial meningitis in Korean adults Antimicrobial resistance of S. pneumoniae isolates 60% R to penicillin 40% NS to 3 rd G. cephalosporins Moon SY, Chung DR, et al. Eur J Clin Microbiol Infect Dis 2010;29:793
CASE 1 CSF culture Listeria monocytogenes
CASE 1 What will you prescribe for definitive antibiotic therapy based on the culture report? 1) Ceftriaxone 2) Vancomycin 3) Metronidazole 4) Ampicillin 5) Ciprofloxacin
CASE 2 M/76 CC: Lower back pain (onset: 8 days PTA) PI: Physical exam. Systolic heart murmur Mild percussion tenderness at lower back no fever but taking NSAIDs Weight loss of 3 kg since 3 months ago Small purpuric rash on finger tips 3 MA PMHx: Valvular heart disease
CASE 2
CASE 2 Echocardiography: Moderate eccentric MR d/t anterolateral commissure prolapse Multiple vegetations at mitral valve
CASE 2 What will you prescribe for empirical antimicrobial therapy in this patient? 1) Penicillin G 2) Ceftriaxone 3) Vancomycin 4) Ceftriaxone + ampicillin 5) Nafcillin + vancomycin
CASE 2 Blood culture : Enterococcus faecalis --------------------------------------------------------------------------- Antibiotics MIC Susceptibility -------------------------- -------- -------------- Benzylpenicillin 4 S Ampicillin <=2 S Ampicillin/Sulbactam <=2 S Imipenem <=1 S Gentamicin High Level (synergy) R Streptomycin High Level (synergy) S Ciprofloxacin 1 S Levofloxacin 1 S Quinupristin/Dalfopristin 2 R Linezolid 2 S Teicoplanin <=0.5 S Vancomycin 1 S Tigecycline <=0.12 S
CASE 2 What will you prescribe for definitive antibiotic therapy based on the culture report? 1) Nafcillin 2) Ampicillin/sulbactam 3) Ceftriaxone 4) Vancomycin 5) Ampicillin + streptomycin (i.m.)
E. coli Antimicrobial susceptibility test CASE 2 (mg/ml) 18
Minimal Inhibitory Concentration (MIC) Broth dilution test 10 5 10 6 bacteria/ml, overnight culture 0.5 1 2 4 8 16 32 64 mg/ml Antibiotics MIC =? 19
E. coli Antimicrobial susceptibility test (mg/ml)? 20
Concentration (mg/ml) Relationship between pk of an antibiotic and susceptibility 5 4 3 MIC of organism A 2 1 MIC Breakpoint organism C 0 Time (h) organism B 21
Minimal Bactericidal Concentration (MBC) 4 8 16 32 Overnight incubation 64 (mg/ml) Antibiotic-free agar containing media MBC =? 22
Enterococcus faecalis Antibiotics MIC (mg/ml) MBC (mg/ml) Penicillin 0.4 12.5 > 6.25 (>100 in 80%) Ampicillin <0.4 3.1 Cephalothin 12.5 25 > 100 Vancomycin 0.78 3.1 > 100 Intrinsic Resistance Penicillin, ampicillin, vancomycin: bacteriostatic Cephalosporins against enterococci Methicillin Infection site requiring bactericidal Aminoglycosides agents? Combination with AGs Acquired Synergy Resistance Ampicillin High or Level Penicillin Resistance G to AGs Vancomycin or teicoplanin HLR to Aminoglycosides 항생제의사용원칙 23
In vitro and Animal Models of Antibiotic Synergy Studies on Antibiotic Synergism against Enterococcus Amikacin Ampicillin Ampicillin + Amikacin Iannini PB, et al. Antimicrob Agents Chemother 1976;9:448 51 24
In vitro and Animal Models of Antibiotic Synergy Studies on Antibiotic Synergism against Enterococcus Effect of antibiotics on the uptake of 14 C-labeled streptomycin by enterococci PCN + SM Vancomycin + SM SM SM Moellering RC, et al. J Clin Invest 1971;50:2580 4 25
CASE 3 F/43 CC: Upper back swelling after bug bite PI: Previously healthy Painful swelling of upper back days after bug bite Physical exam. 38.5 C 3 cm-sized erythematous swelling with fluctuance, upper back Gram stain of aspirated pus Gram positive cocci in clusters Not improved despite oral antibiotics (cefadroxil) for 5 days Febrile
CASE 3 What will you prescribe for empirical antimicrobial therapy in this patient? 1) Penicillin G 2) Nafcillin 3) Vancomycin 4) Ampicillin/sulbactam 5) Clindamycin
CASE 3 Staphylococcus aureus 28
MRSA prevalence in hospitals Korea Japan Taiwan HK Thailand Vietnam Malta Sri Lanka unknown Singapore < 1 % 1-5 % 5-10 % 10-25 % 25-50 % > 50 % Stefani S, Chung DR, et al. Int J Antimicrob Agents 2012;39:273-82 Grundmann H et al. Lancet 2006;368:874-85 Song JH, et al. ANSORP surveillance (2005-2006) Annual report of the EARS-Net. 2009. Mejia C, et al. Braz J Infect Dis 2010;14 (Suppl 2):S79-S86. 29
Evolution of antimicrobial-resistant S. aureus Hospitals Community Hospitals Community McDonald LC. Clin Infect Dis 2006;42:S65-71
Intercontinental Exchanges of CA-MRSA Clones ST72 ST8, ST59, ST80, ST30 DeLeo FR, et al. Lancet 2010; 375: 1557 68 31
Antimicrobial resistance of S. aureus strains isolated from multicenter bacteremia study in Korea (2012-13) Antimicrobial agents CA (N=61) Resistance rate (%) CO HCA (N=107) HO (N=201) Penicillin 85.2 92.5 91.5 Oxacillin 35.5 50.5 75.1 Ciprofloxacin 11.3 43.0 60.7 Clindamycin 16.4 25.2 34.3 Cotrimoxazole 3.3 4.7 3.5 CA: Community-associated CO HCA: Community-onset Healthcare-associated HO: Hospital onset Chung DR, 질병관리본부용역연구보고서 32
Distribution of genotype among MRSA isolates from carriers admitting to the SMC 0.9% 0.9% ST1, 6.4% 0.9% 11.3% [ 범주이름 ] [ 백분율 ] ST5, 28.5% ST72, 46.0% Chung DR, Unpublished 33