Klasik β-laktamaz İnhibitör Kombinasyonları
Özet
β-laktamlar, yetmiş yılı aşkın süredir en çok kullanılan antibiyotik grubudur. Bakterilerin β-laktamaz enzimleri aracılığıyla geliştirdiği direnç nedeniyle etkinliklerini giderek kaybetmektedirler. Bu küresel tehdide karşı geliştirilen en önemli stratejilerden biri, β-laktam antibiyotikleri bu enzimleri inaktive eden inhibitörlerle kombine etmektir. Bir oksapenem olan klavulanik asit ve penisilanik asit sülfonları olan sulbaktam ile tazobaktam, hedef BL enzimlerini kovalent olarak bağlayarak kalıcı bir şekilde inaktive eden "intihar molekülleri" olarak görev yaparlar. Klavulanik asit, toplum kökenli enfeksiyonlarda amoksisilin ile kombine kullanılırken, sulbaktam, Acinetobacter baumannii'ye karşı gösterdiği içsel antibakteriyel aktivite ile diğerlerinden ayrılır ve çoklu ilaç dirençli A. baumannii enfeksiyonların tedavisinde kullanılabilir. Tazobaktam ise piperasilin ile kombinasyon halinde, geniş spektrumu ve düşük AmpC indüksiyon potansiyeli ile ciddi nozokomiyal enfeksiyonların ampirik tedavisinde kilit bir rol oynamaktadır. Bu derlemede, bu alandaki öncü moleküller olan klasik β-laktamaz inhibitörleri; klavulanik asit, sulbaktam ve tazobaktamın mikrobiyolojik özellikleri, etki mekanizmaları, klinik kullanım alanları ve onlara karşı gelişen direnç mekanizmaları ayrıntılı olarak incelenecektir.
β-lactams have been the most widely used group of antibiotics for over seventy years. However, their effectiveness has been gradually diminishing due to bacterial resistance mediated by β-lactamase enzymes. One of the most significant strategies developed to counter this global threat is the combination of β-lactam antibiotics with inhibitors that inactivate these enzymes. Clavulanic acid, an oxapenem, and sulbactam and tazobactam, which are penicillanic acid sulfones, act as “suicide molecules” by covalently binding to and irreversibly inactivating target β-lactamase enzymes. Clavulanic acid is used in combination with amoxicillin for the treatment of community-acquired infections, whereas sulbactam differs from the others with its intrinsic antibacterial activity against Acinetobacter baumannii and can be used in the treatment of multidrug-resistant A. baumannii infections. Tazobactam, in combination with piperacillin, plays a key role in the empirical treatment of serious nosocomial infections due to its broad spectrum and low AmpC induction potential. This review provides a detailed overview of the microbiological characteristics, mechanisms of action, clinical applications, and emerging resistance mechanisms associated with the classical β-lactamase inhibitors-clavulanic acid, sulbactam, and tazobactam.
Referanslar
Perry CM, Markham A. Piperacillin/Tazobactam: An Updated Review of its Use in the Treatment of Bacterial Infections. Drugs. 1999;57(5):805-843.
Egorov AM, Ulyashova MM, Rubtsova MYu. Inhibitors of β-Lactamases. New Life of β-Lactam Antibiotics. Biochemistry (Moscow). 2020;85(11):1292-1309.
Carcione D, Siracusa C, Sulejmani A, Leoni V, Intra J. Old and New Β-Lactamase Inhibitors: Molecular Structure, Mechanism of Action, and Clinical Use. Antibiotics (Basel). 2021;10(8):995.
Shields RK, Doi Y. Penicillins and β-Lactamase Inhibitors. In: Cohen J, Powderly WG, Opal SM, editors. Infectious Diseases. 4th ed. Philadelphia (PA): Elsevier; 2017.
Crass RL, Pai MP. Pharmacokinetics and Pharmacodynamics of β-Lactamase Inhibitors. Pharmacotherapy. 2019;39(2):182-195.
Ku YH, Yu WL. Cefoperazone/sulbactam: New composites against multiresistant gram negative bacteria? Infect Genet Evol. 2021;88:104707.
Khanna NR, Gerriets V. ß-Lactamase Inhibitors. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
Drawz SM, Bonomo RA. Three decades of β-lactamase inhibitors. Clin Microbiol Rev. 2010;23(1):160-201.
Peechakara BV, Gupta M. Ampicillin/Sulbactam. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
Uto LR, Gerriets V. Clavulanic Acid. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
National Institute of Diabetes and Digestive and Kidney Diseases. Ticarcillin-Clavulanate. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012.
Referanslar
Perry CM, Markham A. Piperacillin/Tazobactam: An Updated Review of its Use in the Treatment of Bacterial Infections. Drugs. 1999;57(5):805-843.
Egorov AM, Ulyashova MM, Rubtsova MYu. Inhibitors of β-Lactamases. New Life of β-Lactam Antibiotics. Biochemistry (Moscow). 2020;85(11):1292-1309.
Carcione D, Siracusa C, Sulejmani A, Leoni V, Intra J. Old and New Β-Lactamase Inhibitors: Molecular Structure, Mechanism of Action, and Clinical Use. Antibiotics (Basel). 2021;10(8):995.
Shields RK, Doi Y. Penicillins and β-Lactamase Inhibitors. In: Cohen J, Powderly WG, Opal SM, editors. Infectious Diseases. 4th ed. Philadelphia (PA): Elsevier; 2017.
Crass RL, Pai MP. Pharmacokinetics and Pharmacodynamics of β-Lactamase Inhibitors. Pharmacotherapy. 2019;39(2):182-195.
Ku YH, Yu WL. Cefoperazone/sulbactam: New composites against multiresistant gram negative bacteria? Infect Genet Evol. 2021;88:104707.
Khanna NR, Gerriets V. ß-Lactamase Inhibitors. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
Drawz SM, Bonomo RA. Three decades of β-lactamase inhibitors. Clin Microbiol Rev. 2010;23(1):160-201.
Peechakara BV, Gupta M. Ampicillin/Sulbactam. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
Uto LR, Gerriets V. Clavulanic Acid. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
National Institute of Diabetes and Digestive and Kidney Diseases. Ticarcillin-Clavulanate. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012.
