TỐI ƯU HÓA LIỀU DÙNG KHÁNG SINH Ở TRẺ EM

DANH MỤC CHIA SẼ
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Tổng hợp: DS, CKI.Đặng Ngọc Thạch

1. Giới thiệu

Thuốc kháng sinh là một trong những loại thuốc được dùng phổ biến nhất ở trẻ em. Trong các
thiết lập cấp cứu tại Hoa Kỳ, thuốc kháng sinh được kê toa trong nhiều nhất là một trong năm
lần khám nhi [1]. Nghiên cứu tỷ lệ nhiễm chéo đã chỉ ra rằng hơn 35% – 40% trẻ em nhập
viện đang nhận kháng sinh tại bất kỳ thời điểm nào tại các quốc gia châu Âu [2].

Trong khi việc sử dụng kháng sinh một cách thận trọng rõ ràng là cần thiết trong tất cả các thiết lập dành cho trẻ em, việc lựa chọn thuốc thích hợp và tối ưu hóa liều cũng rất quan trọng để cải thiện việc quản lý nhiễm khuẩn. Một sự hiểu biết về nguyên tắc dược động học/dược động học (PK/PD) có thể cho phép lựa chọn loại thuốc tốt nhất để điều trị một loại vi khuẩn cụ thể trong khi sử dụng chế độ liều lý tưởng để loại trừ nhiễm trùng, hạn chế độc tính và giảm sự phát triển của kháng vi khuẩn.

Như Tiến sĩ Abraham Jacobi chính thức thừa nhận hơn 100 năm trước, trẻ em không phải là người lớn thu nhỏ. Phản ứng với các loại thuốc khác nhau tùy thuộc vào chức năng của cơ quan, kích thước và độ trưởng thành của trẻ [3]. Sự khác biệt liên quan đến tuổi trong hấp thụ, phân bố, chuyển hóa và thải trừ, bằng cách tiếp cận một liều phù hợp cho kê đơn thuốc ở trẻ em [4]. Ngoài ra, có những quần thể đặc biệt trong nhi khoa: những người có bệnh nghiêm trọng, xơ nang, béo phì, suy giảm miễn dịch… sử dụng những phác đồ dùng thuốc theo tuổi ‘chuẩn’ có thể không đủ. Các nhóm này thường yêu cầu liều kháng sinh tối ưu để đảm bảo loại bỏ nhiễm trùng và hạn chế sự phát triển của mầm bệnh kháng thuốc. Do đó, điều quan trọng là phải hiểu và áp dụng các nguyên tắc PK/PD khi sử dụng kháng sinh và đánh giá các phác đồ liều lượng có thể được cá nhân hóa để tối ưu hóa trị liệu ở những bệnh nhân dễ bị tổn thương này. Mục tiêu của tổng quan này là cung cấp một cái nhìn tổng quan chung về các nguyên tắc PK/PD và để thảo luận cách thức các chiến lược có thể được sử dụng trong thực hành lâm sàng để tối ưu hóa liệu pháp kháng sinh ở bệnh nhi.

2. Dược động học (PK) / dược lực học (PD) của thuốc kháng sinh

Dược động học dùng để chỉ nồng độ thuốc trong huyết thanh, các mô và các dịch cơ thể khác theo thời gian và phụ thuộc vào sự hấp thu, chuyển hóa, phân phối và thải trừ. Dược lực học biểu thị các tác dụng dược lý của thuốc đối với một liều nhất định. Trong khi dược động học phụ thuộc vào yếu tố bệnh nhân, dược lực học kháng khuẩn cũng liên quan đến tác nhân gây bệnh. Tính nhạy cảm của vi khuẩn đối với việc giết chết kháng sinh có thể thay đổi rất lớn dựa trên cơ thể sinh vật và tác nhân gây bệnh. Theo truyền thống, khi đo nồng độ tối thiểu của thuốc cần thiết để ức chế sự phát triển của vi khuẩn, được gọi là nồng độ ức chế tối thiểu (MIC), là thông số PD thường được sử dụng lâm sàng để mô tả hoạt tính kháng sinh chống lại tác nhân gây bệnh. Kiến thức về MIC một mình không thể dự đoán thành công của kháng sinh vì MIC không tính đến các quá trình động học trong cơ thể ảnh hưởng đến việc diệt khuẩn theo thời gian. Tích hợp dược động học (phơi nhiễm) và dược lực học (hoạt tính kháng khuẩn) tại vị trí nhiễm trùng nhằm dự đoán hiệu quả của tác nhân chống lại bất kỳ mầm bệnh nào.

Các tác dụng kháng khuẩn thường được mô tả là phụ thuộc vào nồng độ hoặc phụ thuộc vào thời gian [5,6]. Các thuốc phụ thuộc nồng độ tiêu diệt tối đa vi khuẩn với nồng độ ngày càng tăng, trong khi đó các thuốc phụ thuộc thời gian có tác dụng tăng và hiệu quả nhất khi tiếp xúc kéo dài. Một số thuốc cũng có tác dụng kéo dài hoặc hậu kháng sinh (PAE), đề cập đến sự ức chế liên tục sự phát triển của vi khuẩn sau khi loại bỏ thuốc, sự thay đổi dựa trên cơ chế tác dụng của thuốc, tác nhân gây bệnh và cách dùng thuốc [7,8]. Do đó, dựa trên điều kiện diệt khuẩn tối ưu, kháng sinh có thể được chia thành ba loại (Bảng 1): kháng sinh phụ thuộc nồng độ với các PAE vừa phải liên tục; kháng sinh phụ thuộc vào thời gian với các tác dụng diệt khuẩn tối thiểu không liên tục và kháng sinh phụ thuộc vào thời gian với các hiệu ứng dai dẳng kéo dài [10]. Các chỉ số PK / PD tương quan với hiệu quả lâm sàng khác nhau tùy thuộc vào cơ chế hoạt động của thuốc chống vi trùng. Hiểu được thể loại nào mô tả đúng nhất một cơ chế của nhóm kháng sinh cho phép điều chỉnh liều hợp lý để tối đa hóa hoạt động.

Bảng 1. Mô hình hoạt động của các loại thuốc kháng khuẩn khác nhau và dược động học / dược lực học liên quan (PK / PD) đến hiệu quả a.

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Cmax, nồng độ tối đa trong huyết thanh; MIC, nồng độ ức chế tối thiểu; AUC0–24 , diện tích dưới đường cong nồng độ trong khoảng thời gian 24 giờ; T > MIC , tỷ lệ phần trăm của khoảng thời gian dùng thuốc trên MIC.
a Phù hợp với sự cho phép của Taylor và Francis Group LLC Books [ 10 ].
b T > MIC cũng đã được báo cáo là một mục tiêu PK / PD thích hợp cho linezolid [ 9 ].

Trong lịch sử, các mối quan hệ PK/PD đã được xác định từ các mô hình nhiễm trùng trong ống nghiệm hoặc động vật [11] và được xác nhận trong các thử nghiệm của bệnh nhân người lớn [10]. Các nghiên cứu chứng thực các điểm cuối PK/PD trong quần thể trẻ em thường thiếu. Tuy nhiên, cơ chế hoạt động và các thông số PK/PD có tương quan với hiệu quả điều trị các bệnh nhiễm trùng cụ thể ở người lớn về mặt lý thuyết nên tương tự đối với trẻ em. Có ba thông số PK/PD chính thường được mô tả là mục tiêu lâm sàng cho tiếp xúc kháng sinh vì chúng được chứng minh là có hiệu quả lâm sàng đối với các loại kháng sinh khác nhau (Hình 1): nồng độ tối đa trong huyết thanh (C max) đến tỷ lệ MIC (C max/ MIC) cho các loại thuốc phụ thuộc nồng độ; tỷ lệ phần trăm của khoảng thời gian dùng thuốc trên MIC (T > MIC) đối với các loại thuốc phụ thuộc vào thời gian có tác dụng kéo dài đến không có tác dụng kéo dài và tỷ lệ diện tích dưới đường cong của nồng độ thuốc trong khoảng thời gian 24 giờ (AUC 0–24) đến tỷ lệ MIC (AUC 0–24 /MIC) đối với các thuốc phụ thuộc vào thời gian có tác dụng kéo dài vừa phải. Điều quan trọng cần lưu ý là các phân tử thuốc gắn với protein huyết tương không được tự do tác động lên vi khuẩn, do đó các thông số PD thường liên quan đến phần miễn dịch của thuốc trong huyết thanh [12]. Trong phần tiếp theo, chúng tôi sẽ thảo luận về từng loại tác dụng kháng khuẩn cụ thể hơn, sử dụng các ví dụ cụ thể để chứng minh cách thức thông tin PK/PD có thể ảnh hưởng đến tối ưu hóa liều trong thực hành lâm sàng cho trẻ em.

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Hình 1. Quan hệ dược động học/dược lực (PK/PD) giữa nồng độ kháng sinh liên quan đến nồng độ ức chế tối thiểu (MIC) theo thời gian. Ba thông số PK/PD nguyên tắc thường tương quan với hiệu quả lâm sàng của các loại kháng sinh khác nhau: (1) nồng độ tối đa ( C max ) / MIC đối với các thuốc phụ thuộc nồng độ; (2) tỷ lệ phần trăm của khoảng thời gian dùng thuốc trên MIC ( T > MIC ) đối với các loại thuốc phụ thuộc vào thời gian với các hiệu ứng không liên tục tối thiểu; và (3) diện tích theo đường cong nồng độ thời gian (AUC, khu vực bóng mờ) / MIC đối với các thuốc phụ thuộc vào thời gian có tác dụng kéo dài vừa phải kéo dài.

Trước khi tiến hành, hai điểm quan trọng cần được chuyển tải. Đầu tiên, các thông số PK/PD có liên quan rất cao: các điều chỉnh liều ảnh hưởng đến nhiều thông số PK/PD cùng một lúc. Ví dụ, một liều cao hơn sẽ làm tăng C max và AUC 0–24 liên quan đến MIC, cũng như T>MIC . Do đó, nhiều thông số PK/PD có thể tương quan với hiệu quả, tùy thuộc vào cơ chế hoạt động của kháng sinh. Dược động học của thuốc sẽ tác động đến mức độ thay đổi liều ảnh hưởng đến mỗi thông số PK/PD.

Thứ hai, nó là rất quan trọng để nhận ra rằng MIC của một vi khuẩn ảnh hưởng mạnh mẽ đến khả năng đạt được mục tiêu PK/PD trong thực hành lâm sàng. Sự gia tăng nhỏ trong MIC ảnh hưởng đáng kể đến tỷ lệ Cmax /MIC và AUC 0–24 /MIC và T > MIC cho bất kỳ tiếp xúc nào. Đối với các vi khuẩn nhạy cảm cao, ngay cả liều tối ưu/ dưới mức tối ưu cũng có thể là đủ. Tuy nhiên, trong các vi khuẩn có tính nhạy cảm hoặc kháng thuốc giảm, liều dùng kháng sinh thích hợp là điều tối quan trọng để điều trị thành công.

3. Kháng sinh với việc diệt khuẩn phụ thuộc nồng độ với tác dụng vừa phải liên tục

Có hai loại kháng sinh chính được sử dụng trong nhi khoa thể hiện sự tiêu diệt phụ thuộc vào nồng độ của vi khuẩn, cụ thể là aminoglycosides và fluoroquinolones. Các thuốc khác, như ketolides, daptomycin và metronidazole, cũng hoạt động theo cách này [10]. Các thuốc phụ thuộc nồng độ biểu hiện hoạt động diệt khuẩn tối đa ở nồng độ cao nhất và PAE, ức chế sự phát triển của vi khuẩn sau khi nồng độ giảm xuống dưới MIC của vi khuẩn. Những đặc tính này cho phép sử dụng các phác đồ dùng thuốc nhằm tối đa hóa nồng độ (liều cao) trong khi lợi dụng tác dụng kéo dài của thuốc (liều dùng trong thời gian dài). Tối ưu hóa các thuốc kháng sinh phụ thuộc vào nồng độ theo cách này không chỉ thúc đẩy hiệu quả tối đa mà còn có thể ngăn ngừa sự phát triển kháng thuốc và các phản ứng bất lợi. Như aminoglycosides là thuốc kháng sinh phụ thuộc nồng độ sử dụng rộng rãi nhất ở bệnh nhi, liều tối ưu của nhóm này sẽ được thảo luận.

3.1. Aminoglycosides

Có nguồn gốc từ Streptomyces spp., Aminoglycosides đã được sử dụng ở bệnh nhân nhi trong hơn 60 năm. Rất nhiều tài liệu liên quan đến tiện ích lâm sàng, cơ chế hoạt động, dược động học, dược lực học và độc tính của nhóm aminoglycosides [13-15]. Các aminoglycoside được mô tả tốt nhất trong dân số nhi là gentamicin, mặc dù nó chỉ chiếm một phần nhỏ trong nhóm lớn không đồng nhất về cấu trúc. Aminoglycosides gợi ra tác dụng của chúng bằng cách gắn kết không thể đảo ngược với RNA ribosome 16S của tiểu đơn vị vi khuẩn 30S ribosome, do đó ức chế tổng hợp protein. Nồng độ đỉnh trong huyết thanh luôn xảy ra ở phần cuối của truyền tĩnh mạch (iv), cho phép đo trực tiếp Cmax sau khi truyền và giai đoạn phân phối, nơi thuốc khuếch tán từ huyết tương vào các mô. Những loại thuốc này chứng tỏ một phạm vi rộng của vi khuẩn Gram âm, cũng như tác dụng hiệp đồng chống lại các sinh vật Gram dương chọn lọc.

Moore và cộng sự, lần đầu tiên mô tả mối liên quan giữa kết quả bệnh nhân được cải thiện và tỷ lệ C max / MIC cao hơn đối với aminoglycosides [16], chứng minh đáp ứng được cải thiện ở người trưởng thành với nhiễm Gram âm khi tỷ lệ C max / MIC là 8-10. Mục tiêu PK/PD này đã được tái tạo trong một số nghiên cứu khác ở người lớn [17,18] và thường được sử dụng khi bắt đầu phác đồ liều PK cá nhân ở trẻ em. Các chiến lược liều lượng tối ưu bao gồm liều cao dùng mỗi ngày một lần [19,20]. Việc sử dụng liều kéo dài này có lợi thế về hoạt tính diệt khuẩn phụ thuộc vào nồng độ của thuốc và được hỗ trợ lâm sàng bởi PAE và tăng bạch cầu đáng kể, giảm thiểu sự tái phát của vi khuẩn sau khi nồng độ trong huyết thanh giảm xuống dưới MIC [14]. Liều định kỳ mở rộng cũng đề cập đến quá trình PD được gọi là kháng thích ứng, trong đó vi khuẩn phát triển trở kháng có thể đảo ngược đối với hành động diệt khuẩn của thuốc. Nó cho phép giải phóng hoàn toàn các loại thuốc theo thời gian thích hợp cho các vi khuẩn mục tiêu trở lại giai đoạn nhạy cảm và giảm thiểu các biến chứng tiềm ẩn gây ra bởi sự phát triển kháng thuốc.

Mối quan tâm xung quanh thận và độc tính giới hạn của aminoglycoside để sử dụng trong các bệnh nhiễm trùng đáng kể về mặt lâm sàng, đặc biệt là các sinh vật kháng đa thuốc (MDR). Độc tính trên thận có liên quan đến sự tích lũy thuốc, xảy ra do sự gắn kết của thuốc với tế bào thận [21]. Nồng độ duy trì thấp dẫn đến sự hấp thu hiệu quả hơn trong các mô này khi tiếp xúc với các mức liên tục cao [20]. Độc tính trên tai là do sản xuất các gốc tự do gây tổn thương tế bào ốc tai và tế bào tiền đình [22]. Độc tính trên tai thường không thể phục hồi, và độc tính trên thận, trong khi có thể đảo ngược trong phần lớn các trường hợp, có thể dẫn đến nhập viện kéo dài và tăng chi phí bệnh viện ở trẻ em và người lớn [23]. Liều PK cá nhân đã được chứng minh là làm giảm tỷ lệ nhiễm độc thận [24,25] .

Ghi nhận về sự khác biệt trong các thông số PK/PD đối với aminoglycosides ở trẻ em cho phép sẵn sàng áp dụng các chiến lược tối ưu hóa liều. Ví dụ, các chiến lược dùng thuốc ở trẻ sinh non được điều khiển chủ yếu bằng những cân nhắc về PK. Việc thiếu chức năng thận trưởng thành trong dân số này làm chậm quá trình giải phóng thuốc, kéo dài thời gian bán hủy dự kiến từ 2-3 giờ đến 8-12 giờ. Điều này có thể dẫn đến nồng độ đáy cao hơn, làm tăng nguy cơ độc tính nếu không có thay đổi khoảng thời gian định lượng được thực hiện. Trẻ sinh non cũng thể hiện nồng độ đỉnh thấp hơn do thể tích phân bố tương đối lớn hơn (Vd) [26] và mô hình PK hỗ trợ dùng liều cao hơn ở tần suất thấp hơn trong dân số này, chẳng hạn như 24–48 giờ [19].

Trong trường hợp dùng gentamicin cho nhiễm trùng huyết sơ sinh, nồng độ đỉnh trong huyết thanh mục tiêu phải > 8-10 μg/mL khi điều trị các vi sinh vật với MIC ≤1 μg / mL và nồng độ đáy mục tiêu phải <0,5–1 μg/mL trước để tái định lượng [19,20]. Điều này đại diện cho một ví dụ điển hình cho các tiện ích tối ưu hóa liều cá nhân, như sự thích ứng được cá nhân hóa cải thiện kết quả bằng cách giảm độc tính và giảm chi phí chăm sóc sức khỏe [27]. Các bác sĩ lâm sàng thường có được những nồng độ này sau liều thứ ba đến thứ tư, chờ đợi các mức của bệnh nhân để đạt được nồng độ trạng thái ổn định gần đúng. Tuy nhiên, thực hành này có thể trì hoãn các thay đổi liều cần thiết khi điều trị nhiễm trùng được ghi nhận. Sử dụng các mô hình PK dân số phù hợp và kiểm soát thích nghi Bayes có thể cá nhân hóa lịch dùng thuốc ngay khi nhu cầu lâm sàng cho một đợt điều trị kháng sinh kéo dài được xác định, tối đa hóa hiệu quả lâm sàng của thuốc và giảm thiểu độc tính tiềm tàng [28].

Bệnh nhân xơ nang (CF) cũng được hưởng lợi từ liều dùng kéo dài, mặc dù vì những lý do khác nhau hơn so với những người ở trẻ sơ sinh. Vai trò của liệu pháp aminoglycoside ở bệnh nhân CF là để chống lại sinh vật Gram âm, đặc biệt là Pseudomonas aeruginosa. Liều cao hơn là cần thiết ở những bệnh nhân có CF vì ba lý do: (i) vi khuẩn mang bởi bệnh nhân CF thường biểu hiện giảm tính nhạy cảm với các tác nhân kháng khuẩn do tiếp xúc kháng sinh thường xuyên theo thời gian; (ii) bệnh nhân có CF có tổng thanh thải cơ thể cao hơn và lớn hơn Vd so với các bệnh nhân khác và liều cao hơn là cần thiết để đạt được cùng nồng độ trong huyết thanh và (iii) nồng độ cao khó đạt được trong nhiễm trùng phổi so với huyết thanh [29,30]. Việc dùng liều aminoglycosides trong thời gian dài cho phép các bác sĩ điều trị liều lượng lớn, đạt được nồng độ đỉnh cao và tối đa hóa hiệu quả chống lại các sinh vật kháng thuốc [31]. Liều dùng trong thời gian dài cũng cho phép đủ thời gian cho việc thanh thải hoàn toàn thuốc trước khi tái điều trị, do đó làm giảm khả năng nhiễm độc thận. Các nghiên cứu đã chỉ ra rằng liều dùng một lần mỗi ngày là chiến lược định lượng lý tưởng ở những bệnh nhân có CF [32] và điều này hiện được chứng nhận bởi Cystic Fibrosis Foundation như là một chiến lược dùng thuốc ưu tiên [33]. Mặc dù tỷ lệ C max /MIC đã được mô tả là mục tiêu PK/PD tối ưu cho hiệu quả lâm sàng trong điều trị viêm phế quản phổi trong CF [34], không có tỷ lệ đỉnh/ MIC cụ thể nào được xác định rõ ràng.

4. Kháng sinh có hoạt tính diệt khuẩn phụ thuộc vào thời gian với ít ảnh hưởng và không liên tục

Kháng sinh phụ thuộc vào thời gian biểu hiện hoạt tính diệt khuẩn bằng cách duy trì nồng độ trong huyết thanh trên MIC của sinh vật. Một số loại thuốc phụ thuộc vào thời gian có ít tác dụng liên tục và tái phát của hầu hết các sinh vật xảy ra ngay sau khi nồng độ huyết thanh giảm xuống dưới MIC. Đối với kháng sinh trong lớp này, giết chết không được cải thiện ở nồng độ cao hơn và thông số PD liên quan đến hiệu quả là T> MIC, với mục tiêu tối đa hóa thời gian tiếp xúc với thuốc để tối ưu hóa việc tiêu diệt vi khuẩn [6]. β-Lactam là kháng sinh như vậy.

4.1. Kháng sinh β-Lactam

Fleming phát hiện penicillin G vào năm 1928 và lần đầu tiên sử dụng Staphylococcus spp. là vào năm 1941 [35]. Kể từ thời điểm đó, hơn 50 dẫn xuất β-lactam, bao gồm cephalosporin và carbapenems đã được sản xuất, một phần là do nhiều kết hợp hóa học có thể có và hiệu quả của chúng trong việc giết chết nhiều sinh vật khác nhau. Cephalosporin, có tỷ lệ giết chậm, yêu cầu T > MIC 60-70% liều dùng cho hiệu quả tối đa; ít thời gian hơn được coi là chấp nhận được đối với penicillin (50%) và carbapenems (40%), có tỷ lệ giết chết nhanh hơn và PAE dài hơn [6,12]. β-Lactams thường là các thuốc được lựa chọn trong nhi khoa do cấu hình an toàn tương đối cao của chúng và chúng được sử dụng cả trong nhiễm trùng nhi khoa thông thường và nặng. Như một ví dụ về các đặc tính PK / PD của kháng sinh β-Lactam có thể được tối ưu hóa tùy thuộc vào vị trí nhiễm trùng, chúng tôi sẽ đối chiếu việc sử dụng chúng trong viêm tai giữa cấp tính và nhiễm khuẩn huyết.

Các tác nhân gây bệnh phổ biến nhất gây viêm tai giữa cấp tính ở trẻ sơ sinh và trẻ em bao gồm Streptococcus pneumoniae , Haemophilus influenzae và Moraxella catarrhalis . Đề kháng với β-lactam ở S. pneumoniae là do sự thay đổi trong các protein gắn penicillin và có thể được khắc phục theo cách phụ thuộc vào liều. Do sự gia tăng tỷ lệ S. pneumoniae kháng thuốc , liều lượng lớn hơn của penicilin thường được yêu cầu. Các chủng nhạy cảm S. pneumoniae có MIC<2μg/mL đối với iv penicillin, <0,06μg/mL đối với penicillin uống và ≤1,0μg/mL đối với iv cephalosporin với nhiễm khuẩn không viêm màng não [36]. Trung bình, khả năng chữa bệnh bằng vi khuẩn là 80-85% với T> MIC 40-50% và gần 100% với T > MIC 60-70% [37]. May mắn thay, tai giữa có một lớp mao mạch phong phú và một lượng nhỏ dịch kẽ cho phép kháng sinh dễ dàng vượt qua. Điều này dẫn đến phản ứng chậm hơn với những thay đổi về nồng độ trong huyết thanh dẫn đến đỉnh bị cùn và giá trị máng cao [37].. Liều cao hơn của amoxicillin cho hai lần mỗi ngày có thể đạt được độ bão hòa của kháng sinh ở tai giữa và vượt qua sức đề kháng; do đó, phác đồ dùng liều khuyến cáo để điều trị S. pneumoniae kháng penicillin đã trở thành 75–90 mg/kg/ngày [38,39]. Một liều tiêm bắp duy nhất 50mg/kg ceftriaxone sẽ đạt nồng độ chất lỏng trung bình là 9,5 μg/mL ở 72 giờ và 4,8μg/mL ở 96h, đạt T > MIC 100% trong vài ngày ngay cả đối với S. pneumoniae kháng thuốc [37,40].

Khi điều trị nhiễm khuẩn huyết, hoặc nhiễm trùng nghiêm trọng khác, không có không gian thứ ba có sẵn để bão hòa với kháng sinh và hiệu quả lâm sàng phụ thuộc vào nồng độ thuốc tự do trong huyết thanh. Ở những bệnh nhân nguy kịch hoặc suy giảm miễn dịch, trong đó có thể cần thiết để tối đa hóa việc tiêu diệt trong suốt chế độ dùng thuốc, truyền liên tục hoặc kéo dài có thể mang lại lợi ích hơn so với dùng thuốc gián đoạn truyền thống. Việc truyền liên tục với kháng sinh β-lactam trong thời gian dài hoặc liên tục sẽ làm tăng thời gian nồng độ thuốc cao hơn MIC của cơ thể ( Hình 2) và có thể vượt trội hơn so với việc điều trị gián đoạn khi điều trị các mầm bệnh có MIC cao. Một đánh giá hệ thống các thử nghiệm lâm sàng ngẫu nhiên dành cho người lớn được thực hiện bởi Kasiakou và cộng sự, chứng thực giả thuyết này [41]. Ngoài ra, mô phỏng Monte Carlo của trẻ em từ 2 tuổi đến 12 tuổi nhận được một loạt các phác đồ cefepime, ceftazidime, imipenem/cilastatin, meropenem và piperacillin/tazobactam đối với P. aeruginosa với nhiều MIC khác nhau cho thấy đạt được mục tiêu là khó khăn hơn với liều lượng liên tục so với truyền kéo dài hoặc liên tục [42]. Truyền kéo dài β-lactam đã cho thấy lợi ích trong việc giảm tỷ lệ tử vong, thời gian nằm viện và chi phí bệnh viện ở người lớn [43,44]; tuy nhiên, thiếu các nghiên cứu chứng minh ưu thế lâm sàng ở trẻ em. Mặc dù một đánh giá hệ thống gần đây không hỗ trợ sử dụng thường quy ở bệnh nhi [45], các thử nghiệm lâm sàng tiềm năng trong tương lai, được thiết kế tốt sẽ là cần thiết để đánh giá các cách thức truyền kéo dài hoặc liên tục cải thiện kết cục ở bệnh nhi ngoài việc tối ưu hóa việc đạt được mục tiêu PK/PD.

duoc2019_2

Hình 2. Thời gian trên nồng độ ức chế tối thiểu (MIC) để truyền liên tục, kéo dài và liên tục các loại thuốc phụ thuộc vào thời gian. Việc truyền liên tục hoặc kéo dài liên tục các loại thuốc phụ thuộc vào thời gian có thể cải thiện tỷ lệ phần trăm thời gian dùng thuốc trên MIC (T > MIC), đặc biệt là khi điều trị nhiễm trùng có nồng độ MIC cao.

5. Thuốc kháng sinh có hoạt tính diệt khuẩn phụ thuộc vào thời gian với các tác dụng dai dẳng và kéo dài

Trong khi β-lactam cần duy trì nồng độ tự do trên MIC của cơ thể, các kháng sinh phụ thuộc vào thời gian khác có hoạt tính kháng khuẩn bổ sung sau khi nồng độ trong huyết thanh giảm xuống dưới MIC. Các kháng sinh thuộc nhóm này bao gồm macrolides, tetracycline, clindamycin, linezolid và vancomycin. Ví dụ, PAE của vancomycin phụ thuộc vào vi sinh vật và dao động từ 0,7h đến 2,6h đối với Staphylococcus aureus và từ 4,3h đến 6,5h đối với Staphylococcus epidermidis [46]. Do các hiệu ứng ức chế vừa phải liên tục, thông số PK/PD gắn liền với hiệu quả nhất đối với loại kháng sinh này là tỷ số AUC 0-24/MIC [47,48]. Như các ví dụ về các loại kháng sinh này, chúng ta sẽ thảo luận về vancomycin và linezolid và sẽ tương phản với việc sử dụng chúng trong các bệnh nhiễm Gram dương kháng thuốc.

5.1. Vancomycin

Vancomycin là một glycopeptide đã được thương mại hóa để sử dụng từ năm 1958 [49]. Sử dụng lâm sàng là phổ biến trong những năm 1950 với sự xuất hiện của staphylococci sản xuất penicillinase; nó hiện đang được sử dụng thường xuyên do S. aureus kháng meticillin (MRSA). Ở người lớn bị nhiễm MRSA, AUC 0-24/MIC>400 có liên quan đến kết quả lâm sàng được cải thiện [50,51]. Các hướng dẫn thực hành lâm sàng hiện tại để điều trị nhiễm trùng MRSA từ Hiệp hội Bệnh truyền nhiễm Hoa Kỳ (IDSA) khuyến nghị sử dụng phác đồ liều dùng mục tiêu PK/PD này [52,53]. Ở trẻ em bị nhiễm trùng MRSA nghiêm trọng hoặc xâm lấn, bắt đầu sử dụng iv vancomycin 15mg/kg/liều mỗi 6 giờ như một phương tiện để đạt được mục tiêu đó đối với các chủng phân lập với MIC ≤1 μg/mL. Tuy nhiên, dữ liệu ở trẻ em liên kết kết quả được cải thiện với việc đạt được AUC 0-24 /MIC> 400 là thiếu.

Khả năng đạt được AUC 0-24 /MIC> 400 đã được đánh giá trong nhiều mô hình PK dân số trẻ em. Frymoyer và cộng sự nghiên cứu trẻ em từ 2-12 tuổi và dự đoán AUC 0-24 /MIC cho liều vancomycin hàng ngày là 40 mg/kg/ngày và 60 mg/kg/ngày [54]. Các tác giả nhận thấy liều 40mg/kg/ngày không đạt được AUC 0-24 /MIC> 400 với MIC ≥ 1μg/mL, trong khi điều này dễ dàng đạt được hơn với liều 60 mg/kg/ngày [54]. Một mô phỏng Monte Carlo nhắc lại điểm này, với 58-66% trẻ được dự đoán đạt được AUC0-24 /MIC> 400 với liều 40mg/kg/ngày, trong khi liều > 60mg/kg/ngày đạt được mục tiêu này trong 88 –98% trẻ em khi MIC là ≤1 μg/mL [55]. Điều này ít có thể đạt được trong thực hành lâm sàng: Chhim và cộng sự thấy rằng chỉ có 40% trong số 96 trẻ nhận 60mg/kg/ngày vancomycin đạt được AUC 0-24 /MIC> 400 [56].

Các hướng dẫn hiện hành của IDSA cho thấy giá trị đáy 15–20 μg/mL nên được nhắm vào bệnh nhân người lớn bị nhiễm MRSA xâm lấn, vì nồng độ đáy trong phạm vi này tương quan với AUC 0-24 /MIC>400 đối với các chủng phân lập với MIC ≤ 1μg/mL [52]. Đáy 15-20μg/mL thường được chọn ở bệnh nhân nhi đồng, mặc dù có rất ít dữ liệu để hỗ trợ thực hành này. Frymoyer cùng cộng sự. và Le cùng cộng sự gợi ý rằng nồng độ đáy thấp hơn có thể thích hợp ở trẻ em [57,58]. Qua mô hình và mô phỏng PK dân số, Frymoyer và cộng sự thấy rằng đáy 7–10 μg/mL đạt được AUC 0-24 /MIC> 400 trong >90% trẻ em nhận 15 mg/kg/liều mỗi 6 giờ khi MIC là 1μg/mL [57]. Mặt khác, Le và cộng sự sử dụng mô hình PK dựa trên dân số và mô phỏng Monte Carlo để chỉ ra rằng 60–70mg/kg/ngày chia mỗi 6 giờ đạt được mục tiêu AUC 0-24 //MIC> 400 ở 75% bệnh nhân ảo trên một loạt các MIC; AUC 0-24 /MIC> 400 tương ứng với đáy 8–9 μg/mL [58]. Tại Bệnh viện Nhi đồng Cincinnati (Cincinnati, OH), chỉ có 67% trẻ em đạt được 0-24 > 400 khi nồng độ đáy là 8–10μg/mL, cho thấy các nồng độ đáy thấp hơn có thể phù hợp với MIC <1μg/mL nhưng không đầy đủ khi MIC là ≥1 μg/mL [59].

Mặc dù nhắm mục tiêu nồng độ đáy là đơn giản hơn nhiều cho các bác sĩ lâm sàng, nó không phải là rõ ràng rằng các mục tiêu đáy được thành lập ở bệnh nhân người lớn là lý tưởng ở trẻ em. Và trong khi AUC 0-24 /MIC> 400 có liên quan đến kết quả được cải thiện ở bệnh nhân người lớn bị MRSA, thiếu các nghiên cứu nhi khoa và các nghiên cứu tiềm năng là cần thiết để xác nhận mục tiêu PK/PD hiện đang được chấp nhận. Ngoài ra, một số trẻ em có thể chứng minh sự thanh thải nhanh chóng của vancomycin dẫn đến việc sử dụng quá liều và có thể điều chỉnh liều thường xuyên không cần thiết. Trong khi các nghiên cứu trên đưa ra các chủ đề quan trọng để thảo luận, dựa trên dữ liệu vancomycin PK và AUC0-24 chúng tôi không khuyến nghị thay đổi thực hành lâm sàng mà chỉ đơn giản là tìm kiếm các giá trị đáy trong huyết thanh vancomycin thấp hơn. Thay vào đó, cá nhân hóa điều trị y tế và sử dụng thông tin về AUC và MIC cho mỗi người cần vancomycin trong điều trị bệnh tụ cầu khuẩn xâm lấn có thể mang lại kết quả tốt nhất cho bệnh nhân nhi [59].

5.2. Linezolid

Các sinh vật kháng Gram dương như MRSA và enterococci kháng vancomycin (VRE) ngày càng trở nên phổ biến ở trẻ em [60, 61]. Nhiễm trùng MRSA với MIC vancomycin cao (vancomycin-trung gian S. aureus ) và VRE là vấn đề bởi vì chúng khó điều trị và thường mang bệnh suất và tử vong cao hơn so với những người do các chủng nhạy cảm với vancomycin [62]. Các lựa chọn điều trị cho các tác nhân gây bệnh này bị giới hạn; linezolid, một kháng sinh oxazolidinone, được sử dụng rộng rãi nhất ở bệnh nhi. Tác nhân này, ức chế sự tổng hợp protein của vi khuẩn bằng cách ngăn ngừa sự hình thành tiểu đơn vị 70S ribosome của vi khuẩn, có khả năng sinh học cao và có sự thâm nhập mô tuyệt vời, làm cho nó trở thành một thay thế hấp dẫn đối với vancomycin [63-65]. Mặc dù các nghiên cứu đã cho thấy linezolid có hiệu quả như vancomycin trong điều trị nhiễm trùng Gram dương nghiêm trọng [66, 67], việc sử dụng nó nên được giới hạn để duy trì hoạt động chống lại các vi sinh vật kháng thuốc.

Linezolid thể hiện hoạt tính kìm khuẩn chống lại các sinh vật Gram dương như staphylococci và enterococci và là kháng sinh phụ thuộc vào thời gian với PAE vừa phải, được tăng lên ở nồng độ cao hơn so với MIC của vi sinh vật [68]. Một nghiên cứu của Rayner và cộng sự thấy rằng AUC 0-24 /MIC 80-120 và T >MIC > 85% liều dùng có liên quan đến việc điều trị thành công nhiễm khuẩn huyết, nhiễm trùng đường hô hấp dưới, nhiễm trùng da và mô mềm ở những bệnh nhân trưởng thành [69]. Các tác giả cũng nhận thấy rằng mặc dù hoạt tính kìm khuẩn in vitro của linezolid đối với staphylococci và enterococci, việc loại trừ nhiễm khuẩn huyết đã được cải thiện và nhanh hơn khi AUC 0-24 /MIC>105 và T > MIC > 82,1%, kết quả cho thấy hoạt tính diệt khuẩn lâm sàng. Các thông số PK/PD của T>MIC và AUC 0-24 /MIC đã được chứng thực bởi một số nghiên cứu khác [70,71].

Như với nhiều loại thuốc, dược động học của linezolid phụ thuộc vào sự trưởng thành của cơ quan và tăng cân bằng allometric, với độ thanh thải nhanh hơn, AUC nhỏ hơn và thời gian bán hủy thải ngắn hơn ở trẻ em so với người lớn [72,73]. Các nghiên cứu đã xác định rằng liều thường xuyên hơn (mỗi 8h) là cần thiết cho trẻ em <12 tuổi để đạt được tiếp xúc thích hợp. Ở những bệnh nhân bị nhiễm trùng, Vd và độ thanh thải thường tăng lên dẫn đến sự thay đổi đáng kể giữa các thông số PK đối với nhiều loại thuốc, bao gồm cả linezolid [74,75]. Điều này đặc biệt có vấn đề ở trẻ nhỏ bị nhiễm trùng huyết vì việc sử dụng các chế độ dùng thuốc tiêu chuẩn có thể dẫn đến tiếp xúc linezolid và nồng độ thuốc điều trị không đủ. Sử dụng truyền liên tục linezolid có thể thúc đẩy mức độ thuốc nhắm mục tiêu tốt hơn và cải thiện khả năng đạt được mục tiêu PK/PD, cho dù sử dụng AUC 0-24 /MIC 80-120 hoặc T > MIC > 85% [74]. Các chiến lược định lượng linezolid thay thế ở trẻ em bị nhiễm trùng hoặc bị bệnh nghiêm trọng chưa được nghiên cứu chính thức.

Một lần nữa, trẻ bị CF cũng thay đổi dược động học so với các trẻ khác [29,30,76 ]. Giải phóng mặt bằng khi bình thường hóa cho trọng lượng cơ thể thường tăng lên, và những người có CF thường cần tăng liều mg / kg đối với hầu hết các thuốc kháng sinh. Santos et al. xác minh điều này cho linezolid và thấy rằng liều linezolid tiêu chuẩn (10 mg / kg / liều iv mỗi 8 h) là không đủ để đạt được AUC 0-24 / MIC> 80 đối với S. aureus [77]. Vì sự xâm nhập của MRSA và nhiễm trùng đường hô hấp dưới ở bệnh nhi tăng CF, việc khám phá các chiến lược định lượng thay thế trong số bệnh nhân này có thể cần thiết.

Quan trọng hơn, linezolid cũng chứng minh độc tính huyết học phụ thuộc vào liều, với AUC huyết thanh cao hơn và nồng độ đáy cao được liên kết cả với giảm tiểu cầu và thiếu máu [78-80]. Do đó, tiếp xúc thích hợp là tối quan trọng cho cả tối đa hóa hiệu quả và hạn chế độc tính. Truyền liên tục, có thể cho phép dùng liều hàng ngày thấp hơn so với lịch dùng liều cao hơn hoặc thường xuyên hơn, có thể là phương pháp hợp lý để điều trị các vi sinh vật kháng, ở bệnh nhân có thay đổi cấu hình PK, hoặc ở những người có nguy cơ nhiễm độc cao hơn. Một lần nữa, nhiều nghiên cứu ở bệnh nhi là cần thiết.

6. Tương lai kháng thuốc

Để tiếp cận sự đề kháng kháng sinh ở trẻ em, người ta có thể tìm đến các mô hình mới trong dân số người lớn. Năm 2009, IDSA đã báo cáo một danh sách các mầm bệnh có thể được dự kiến sẽ mang lại kỷ nguyên hậu kháng sinh [81]. Một báo cáo của Trung tâm kiểm soát và phòng ngừa dịch bệnh Hoa Kỳ (CDC), ‘ Các mối đe dọa kháng kháng sinh tại Hoa Kỳ, 2013 ‘, nêu chi tiết các tác nhân gây ra mối đe dọa cao nhất do kháng thuốc mới chống lại kháng sinh hiện có [82]. Với sự phát triển thuốc kháng sinh mới giảm, nhu cầu tối ưu hóa liều lượng kháng sinh hiện có tăng lên. Các vi sinh vật Gram dương (VRE và MRSA) có thể được điều trị bằng một số thuốc kháng sinh khi nhạy cảm. Rất ít kháng sinh có thể được sử dụng để điều trị các vi khuẩn kháng thuốc, bao gồm daptomycin, linezolid, quinupristin/dalfopristin, tigecycline và cephalosporin thế hệ thứ năm. Trong số này, rất ít dữ liệu PK/PD được công bố trong cộng đồng nhi khoa.

Các vi khuẩn Gram âm ( Klebsiella spp., Escherichia coli , Acinetobacter baumannii , P. aeruginosa và Enterobacter spp.) có ít lựa chọn điều trị hơn, dẫn đến việc sử dụng các loại thuốc kháng sinh bị bỏ rơi trước đây như colistimethate. Hầu hết các vi khuẩn này đã cho thấy sức đề kháng lâm sàng đối với hầu hết tất cả các loại kháng sinh thông qua việc tạo ra các β-lactamase phổ rộng, carbapenemases hoặc thay đổi trong ái lực liên kết. Mặc dù một số phương pháp điều trị mới cho các vi khuẩn này đang được triển khai, nhưng sẽ có một sự chậm trễ trong nghiên cứu dữ liệu PK/PD ở trẻ em, vì vậy cần nâng cao tầm quan trọng của việc nghiên cứu và áp dụng tối ưu hóa liều dùng kháng sinh hiện tại để tăng hiệu quả và ngăn ngừa kháng thuốc.

Cuối cùng, kiến thức về cách sử dụng kháng sinh một cách thích hợp cũng quan trọng như việc biết nên chọn loại kháng sinh nào. Trong phần lớn các tình huống lâm sàng ở bệnh nhi, việc chọn đúng thuốc là đủ. Tuy nhiên, trong các trường hợp khác như nhiễm trùng huyết (sơ sinh hoặc khác), nhiễm trùng ở bệnh nhân điều trị thay thế thận, viêm phế quản phổi ở bệnh nhân CF, hoặc khi điều trị vi khuẩn MDR ở trẻ suy giảm miễn dịch, liều lượng chính xác của thuốc cũng quan trọng như kháng sinh được chọn. Việc sử dụng các nguyên tắc PK/PD có thể bảo toàn hiệu quả của các loại thuốc hiện có trong cuộc chiến chống lại các sinh vật kháng thuốc. Trong những năm tới, tầm quan trọng của việc tối ưu hóa liều sẽ trở nên rõ ràng hơn.

7. Tối ưu hóa liều cá nhân: một cách tiếp cận thực tế cho dược động học/dược lực học

Trong khi các nghiên cứu PK thường mô tả tác động cơ thể lên thuốc trong quần thể, chúng không nhất thiết đưa ra hướng dẫn cụ thể về liều tối ưu cho từng bệnh nhân. Như với hầu hết các loại thuốc, kháng sinh hiển thị sự thay đổi đáng kể giữa các lần tiếp xúc với thuốc phụ thuộc vào tình trạng cơ bản của bệnh nhân. Liều lượng theo kinh nghiệm dựa trên các nguyên tắc PK/PD sẽ tối đa hóa khả năng đạt được các mục tiêu điều trị. Tuy nhiên, theo dõi thuốc điều trị (TDM) là tối quan trọng để xác định nhu cầu điều chỉnh liều và đảm bảo liều tối ưu trong suốt liệu trình kháng sinh.

TDM chỉ có sẵn cho một số ít thuốc kháng sinh, chẳng hạn như aminoglycosides và vancomycin. Mặc dù có nhiều kiến thức về dược động học của nhiều loại thuốc kháng sinh, tất cả các kháng sinh đều có thể được kê đơn tốt hơn với việc đo trực tiếp nồng độ thuốc. Thông thường, TDM được sử dụng để giảm thiểu độc tính, trong khi hiệu quả gần đúng, do mối quan tâm thực tế và chi phí liên quan. Tuy nhiên, trực tiếp đo nồng độ thuốc có thể được sử dụng để ước tính chính xác hơn việc đạt được mục tiêu PK/PD và để thông báo điều chỉnh liều hợp lý khi cần thiết. Phần mềm định lượng có thể thực hiện hồi quy phi tuyến tính hoặc các kỹ thuật toán học khác như thuật toán Bayes để ước lượng các tham số PK riêng lẻ (AUC, C max) có thể được sử dụng để đạt được các mục tiêu mong muốn cho một loại thuốc nhất định.

Các mô hình dân số cũng có thể hữu ích để tối ưu hóa liệu pháp cá nhân hóa. Những mô hình này cung cấp một bản tóm tắt các ước tính tham số PK trong một quần thể cụ thể và có thể được sử dụng để phát triển một chế độ dùng thuốc có nhiều khả năng đạt được mục tiêu mong muốn dựa trên các đặc điểm lâm sàng của bệnh nhân [ 83]. Khi không có các phép đo nồng độ thuốc, thông tin lâm sàng và nhân khẩu học được kết hợp để cung cấp các phác đồ liều lượng thực nghiệm. Sử dụng nồng độ thuốc làm phản hồi để thông báo cho mô hình cách bệnh nhân xử lý thuốc sẽ tăng độ chính xác của ước lượng tham số PK và cải thiện mục tiêu đạt được. Một loạt các chương trình phần mềm tồn tại để hỗ trợ trong việc xác định các phác đồ thuốc lý tưởng để tối đa hóa khả năng đạt được mục tiêu PK/PD ở những bệnh nhân cụ thể. Những gói này có thể hỗ trợ các nguyên tắc định lượng PK/PD đến giường bệnh.

8. Kết luận

Kiến thức về nguyên tắc PK/PD là rất quan trọng khi kê đơn thuốc kháng sinh ở trẻ em, đặc biệt là khi điều trị nhiễm trùng nghiêm trọng và trong những nhóm trẻ đặc biệt đã thay đổi dược động học. Mặc dù các phác đồ dùng thuốc tiêu chuẩn có thể phù hợp với hầu hết trẻ em, nhưng sự công nhận của những bệnh nhân nào sẽ được hưởng lợi nhiều nhất từ các chiến lược định lượng phi truyền thống là quan trọng. Ngoài ra, khi các bác sĩ nhi khoa tham gia vào cuộc chiến chống lại các vi khuẩn MDR, việc sử dụng kháng sinh dựa trên nguyên tắc PK/PD có thể cho phép tiếp tục sử dụng kháng sinh thông thường và bảo quản các thuốc mới hơn cho những người thực sự thiếu các lựa chọn điều trị khác. Chúng tôi tin rằng tối ưu hóa liều PK/PD là một thành phần quan trọng trong việc kê đơn kháng sinh có tính chất thận trọng, đó là nền tảng của việc quản lý kháng sinh.

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