Bài giảng Dược lý lâm sàng trong sử dụng kháng sinh

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Bài giảng Dược lý lâm sàng trong sử dụng kháng sinh, được biên soạn với mục tiêu nhằm giúp các bạn sinh viên có thể giải thích được các bước tiếp cận hệ thống trong lựa chọn kháng sinh; Thiết kế được chế độ liều trong sử dụng các kháng sinh nhóm betalactam, aminoglycosid và fluorquinolon dựa trên các dữ liệu dược động học và dược lực học;...Mời các bạn cùng tham khảo!

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Nội dung Text: Bài giảng Dược lý lâm sàng trong sử dụng kháng sinh

DƯỢC LÝ LÂM SÀNG TRONG SỬ DỤNG KHÁNG SINH Bộ môn Dược lý Trường Đại học Dược Hà Nội
Mục tiêu học tập 1. Giải thích được các bước tiếp cận hệ thống trong lựa chọn kháng sinh 2. Thiết kế được chế độ liều trong sử dụng các kháng sinh nhóm betalactam, aminoglycosid và fluorquinolon dựa trên các dữ liệu dược động học và dược lực học 3. Phân tích được các giải pháp để hạn chế đề kháng kháng sinh
Nguyên tắc sử dụng kháng sinh • Chỉ sử dụng KS khi có nhiễm khuẩn • Lựa chọn KS hợp lý • Sử dụng KS đúng liều, đúng cách và đủ thời gian • Phối hợp KS hợp lý • Dự phòng KS hợp lý Tiếp cận hệ thống trong lựa chọn kháng sinh điều trị nhiễm khuẩn
Nguyên lý chung trong điều trị nhiễm khuẩn A textbook of Clinical Pharmacology and Therapeutics, 5th Edn
Chẩn đoán nhiễm khuẩn • Xác định nhiễm khuẩn – Sốt > 37oC – Dấu hiệu và triệu chứng… • WBC: tăng, hiếm khi quá 30.000-40.000 tb/mm3 (bình thường 4000-10000 tb/mm3) • Dấu hiệu tại vị trí nhiễm khuẩn • Xác định nguyên nhân gây bệnh – Lấy mẫu bệnh phẩm – Nuôi cấy – Đánh giá độ nhạy cảm – Biện giải kết quả
Test đánh giá nhạy cảm Bán định lượng Susceptible Intermediate Resistant
Test đánh giá nhạy cảm Đĩa khuếch tán
Test đánh giá nhạy cảm Xác định MIC trên đĩa 96 giếng
Test đánh giá nhạy cảm Xác định MIC trên đĩa 96 giếng
Test đánh giá nhạy cảm Epsilometer test (Etest)
Test đánh giá nhạy cảm • Biện giải kết quả – EUCAST (The European Committee on Antimicrobial Susceptibility Testing) – CLSI (Clinical & Laboratory Standards Institute)
SIR – the old definitions Susceptible Intermediate Uncertain effect. Buffer zone for technical variation. For a high dose. Where concentrated for pharmacokinetic reasons. Resistant Redefining S, I and R 2019 - www.eucast.org
SIR - new definitions 2019 Susceptible Resistant Normal Increased exposure exposure Redefining S, I and R 2019 - www.eucast.org
• Ví dụ Guidance on reading EUCAST Breakpoint Tables EUCAST Clinical Breakpoint Tables v. 11.0, valid from 2021-01-01 MIC determination (broth microdilution according to ISO standard 20776-1) Disk diffusion (EUCAST standardised disk diffusion method) Medium: Medium: Inoculum: Inoculum: EUCAST methodology and quality EUCAST methodology and Incubation: Incubation: Reading: control for MIC determination Reading: quality control for disk diffusion Quality control: Quality control: The I category is not listed but is interpreted as the values between the S and the R breakpoints. If the S and R breakpoints are the same value An arbitrary "off scale" Breakpoints with a there is no I category. breakpoint which species name apply Area of Technical Uncertainty categorises wild-type only to that particular Agent A: No I category See specific information on how to organisms as species (in this Agent B: I category: 4 mg/L, 23-25 mm handle technical uncertainty in "Susceptible, increased example S. aureus) Agent H: I category: 1-2 mg/L, 24-29 mm antimicrobial susceptibility testing. exposure (I)". Antimicrobial agent MIC breakpoint Disk Zone diameter breakpoint Notes (mg/L) content (mm) Numbered notes relate to general comments and/or MIC breakpoints. S≤ R> ATU (µg) S≥ R< ATU Lettered notes relate to the disk diffusion method. Antimicrobial agent A 11 11 X 20A 20A 1. Notes that are general comments and/or relating to MIC breakpoints. Antimicrobial agent B 22 4 Y 26 23 2. New comment Removed comment Antimicrobial agent C 0.001 8 X 50 18 Antimicrobial agent D, S. aureus IE IE IE IE A. Comment on disk diffusion Antimicrobial agent E - - - - Antimicrobial agent F IP IP IP IP Antimicrobial agent G (screen only) NA NA Y 25 25 Antimicrobial agent H 0.5 2 Z 30 24 Antimicrobial agent I (8)1 (8)1 30 (18)A (18)A Changes from previous Screening breakpoint to version highlighted in yellow differentiate between Not Applicable isolates without and with (disk screening breakpoint only) No breakpoints. resistance mechanisms Susceptibility testing is not recommended In Preparation MIC breakpoints in blue are linked to MIC distributions Zone diameter breakpoints in blue are linked to zone diameter distributions Breakpoints in brackets are used to Antimicrobial agents in blue distinguish between organisms with and Insufficient evidence that the are linked to EUCAST without acquired resistance mechanisms organism or group is a good rationale documents (see Notes) target for therapy with the agent 10
• Ví dụ Enterobacterales * EUCAST Clinical Breakpoint Tables v. 11.0, valid from 2021-01-01 Expert Rules and Intrinsic Resistance Tables Cephalosporins1 MIC breakpoints Disk Zone diameter Notes (mg/L) content breakpoints (mm) Numbered notes relate to general comments and/or MIC breakpoints. S≤ R> ATU (µg) S≥ R< ATU Lettered notes relate to the disk diffusion method. Cefaclor - - - - 1. The cephalosporin breakpoints for Enterobacterales will detect all clinically important resistance mechanisms Cefadroxil (uncomplicated UTI only) 16 16 30 12 12 (including ESBL and plasmid mediated AmpC). Some isolates that produce beta-lactamases are susceptible to 3rd or 4th generation cephalosporins with these breakpoints and should be reported as tested, i.e. the presence or absence of an Cefalexin (uncomplicated UTI only) 16 16 30 14 14 ESBL does not in itself influence the categorisation of susceptibility. ESBL detection and characterisation are Cefazolin (infections originating from the 0.0012 42 30 50A 20A recommended for public health and infection control purposes. urinary tract), E. coli, and Klebsiella spp. 2/A. Isolates susceptible to cefadroxil and/or cefalexin can be reported "susceptible, increased exposure” (I) to cefazolin. (except K. aerogenes ) 3. Broth microdilution MIC determination must be performed in iron-depleted Mueller-Hinton broth and specific reading Cefepime 1 4 30 27 24 instructions must be followed. For testing conditions and reading instructions, see Cefiderocol 23 23 30 22 22 18-22 http://www.eucast.org/guidance_documents/. Cefixime (uncomplicated UTI only) 1 1 5 17 17 4. The cefoxitin ECOFF (8 mg/L) has a high sensitivity but poor specificity for identification of AmpC-producing 1 2 20 17 Enterobacterales as this agent is also affected by permeability alterations and some carbapenemases. Classical non- Cefotaxime (indications other than 5 AmpC producers are wild type, whereas plasmid AmpC producers or chromosomal AmpC hyperproducers are non-wild meningitis) type. Cefotaxime (meningitis) 1 1 5 20 20 5. For susceptibility testing purposes, the concentration of avibactam is fixed at 4 mg/L. Cefoxitin (screen only)4 Note4 Note4 30 19 19 6. See table of dosages for dosing for different indications. Cefpodoxime 1 1 10 21 21 7. For susceptibility testing purposes, the concentration of tazobactam is fixed at 4 mg/L. (uncomplicated UTI only) Ceftaroline 0.5 0.5 5 23 23 22-23 Ceftazidime 1 4 10 22 19 Ceftazidime-avibactam 85 85 10-4 13 13 Ceftibuten (infections originating from the 1 1 30 23 23 urinary tract) Ceftobiprole 0.25 0.25 5 23 23 Ceftolozane-tazobactam6 27 27 30-10 22 22 19-21 Ceftriaxone (indications other than 1 2 30 25 22 meningitis) Ceftriaxone (meningitis) 1 1 30 25 25 Cefuroxime iv, E. coli, Klebsiella spp. (except 0.001 8 30 50 19 K. aerogenes ), Raoultella spp. and P. mirabilis Cefuroxime oral (uncomplicated UTI only), 8 8 30 19 19 E. coli, Klebsiella spp. (except K. aerogenes ), Raoultella spp. and P. mirabilis
• Ví dụ Enterobacterales * EUCAST Clinical Breakpoint Tables v. 11.0, valid from 2021-01-01 Expert Rules and Intrinsic Resistance Tables Carbapenems1 MIC breakpoints Disk Zone diameter Notes (mg/L) content breakpoints (mm) Numbered notes relate to general comments and/or MIC breakpoints. S≤ R> ATU (µg) S≥ R< ATU Lettered notes relate to the disk diffusion method. Doripenem 1 2 10 24 21 1. Some isolates that produce carbapenemase are categorised as susceptible with the current breakpoints and should be Ertapenem 0.5 0.5 10 25 25 reported as tested, i.e. the presence or absence of a carbapenemase does not in itself influence the categorisation of susceptibility. Carbapenemase detection and characterisation are recommended for public health and infection control Imipenem, Enterobacterales except 2 4 10 22 19 purposes. For carbapenemase screening a meropenem screening cut-off of >0.125 mg/L (zone diameter ATU (µg) S≥ R< ATU Lettered notes relate to the disk diffusion method. Aztreonam1 1 4 30 26 21 1. The aztreonam breakpoints for Enterobacterales will detect clinically important resistance mechanisms (including ESBL). Some isolates that produce beta-lactamases are susceptible to aztreonam with these breakpoints and should be reported as tested, i.e. the presence or absence of an ESBL does not in itself influence the categorisation of susceptibility. ESBL detection and characterisation are recommended for public health and infection control purposes. Fluoroquinolones MIC breakpoints Disk Zone diameter Notes (mg/L) content breakpoints (mm) Numbered notes relate to general comments and/or MIC breakpoints. S≤ R> ATU (µg) S≥ R< ATU Lettered notes relate to the disk diffusion method. Ciprofloxacin 0.25 0.5 0.5 5 25 22 22-24 1. There is clinical evidence for ciprofloxacin to indicate a poor response in systemic infections caused by Salmonella Ciprofloxacin1, Salmonella spp. 0.06 0.06 NoteA NoteA spp. with low-level ciprofloxacin resistance (MIC >0.06 mg/L). The available data relate mainly to Salmonella Typhi but there are also case reports of poor response with other Salmonella species. Pefloxacin (screen only)1,2 NA NA 5 24B,C 24B,C 2/C. The pefloxacin 5 µg breakpoint used to screen for clinical fluoroquinolone resistance in Salmonella spp., can also be Salmonella spp. used to detect fluoroquinolone resistance mechanisms in other Enterobacterales such as E. coli, K. pneumoniae and Delafloxacin, E. coli 0.125 0.125 NoteD NoteD Shigella spp. Levofloxacin 0.5 1 5 23 19 Moxifloxacin 0.25 0.25 5 22 22 A. Tests with a ciprofloxacin 5 µg disk will not reliably detect low-level resistance in Salmonella spp. To screen for Nalidixic acid (screen only) NA NA NA NA ciprofloxacin resistance in Salmonella spp., use the pefloxacin 5 µg disk. See Note B. Norfloxacin (uncomplicated UTI only) 0.5 0.5 10 22 22 B. Susceptibility of Salmonella spp. to ciprofloxacin can be inferred from pefloxacin disk diffusion susceptibility. D. A disk diffusion test is not yet developed. Perform an MIC test. Ofloxacin 0.25 0.5 5 24 22
• Ví dụ: thông tin mục “5. Đặc tính dược lý” trong HDSD của ciprofloxacin (EMC)
to antimicrobial compounds. The zone size should be determined using a standardized test method.6,7,8 This procedure • Ví dụ: thông tin mục “12. Dược lý lâm sàng” trong HDSD của ciprofloxacin (FDA) uses paper disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in Table 12. Table 12: Susceptibility Test Interpretive Criteria for Ciprofloxacin MIC (mcg/mL) Zone Diameter (mm) Bacteria S I R S I R Enterobacteriaceae 2 16–20 Enterococcus faecalis 2 16–20 Staphylococcus aureus 2 16–20 Staphylococcus epidermidis 2 16–20 Staphylococcus saprophyticus 2 16–20 Pseudomonas aeruginosa 2 16–20 Haemophilus influenzae1 - - - - Haemophilus parainfluenzae1 - - - - Salmonella typhi 0.12–0.5 21–30 Streptococcus pneumoniae 2 16–20 Streptococcus pyogenes 2 16–20 Neisseria gonorrhoeae2 0.12–0.5 28–40 Bacillus anthracis1 - - - - - Yersinia pestis1 - - - - - S=Susceptible, I=Intermediate, and R=Resistant. 1. The current absence of data on resistant isolates precludes defining any results other than “Susceptible.” If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. 2. MIC is determined by the agar dilution method
Nguyên lý chung trong điều trị nhiễm khuẩn A textbook of Clinical Pharmacology and Therapeutics, 5th Edn
"HIT HARD & HIT FAST“: nguyên tắc 4D 4D = chọn đúng kháng sinh theo phổ tác dụng, vị trí nhiễm khuẩn và nguy cơ nhiễm VK kháng thuốc, phối hợp kháng sinh hợp lý, liều dùng/chế độ liều phù hợp (PK/PD), xuống thang đúng cách Denny KJ et al. Expert Opin. Drug Saf. 2016; 15: 667-678.