Grup 2a β-laktamazlar
Özet
Grup 2a β-laktamazlar, Ambler sınıflamasında A sınıfında yer alan ve dar spektrumlu penisilinazları kapsayan enzimlerdir. Temel temsilcisi PC1 olup özellikle benzilpenisilin ve türevlerini hidrolize ederken sefalosporinlere, karbapenemlere ve monobaktamlara düşük düzeyde etkilidir. Penisilinin 1940’larda klinik kullanıma girmesinden kısa süre sonra stafilokoklarda hızla penisilin direnci gelişmiş ve bu direnç penisilinaz üretimine bağlanmıştır. 2000’li yıllara gelindiğinde farklı coğrafyalardan toplanan metisiline duyarlı Staphylococcus aureus (MSSA) izolatlarının %80’den fazlasında blaZ penisilinaz geni bulunmuştur. S. aureus’ta penisilin direncinin iki ana mekanizması vardır: blaZ geni aracılığıyla penisilinaz üretimi ve mecA aracılığıyla PBP2a sentezi. blaZ geninin A–D tipleri tanımlanmıştır; bunlardan özellikle tip A ve C klinik açıdan önemlidir. Bu enzimler sefazolin tedavisinde “inokülum etkisi” (CzIE) ile ilişkilendirilmiş olup tedavi başarısızlıklarına yol açabilmektedir. Latin Amerika’da yapılan geniş bir çalışmada tip C ilk (%37), tip A ise ikinci sırada bulunmuş, CzIE prevalansı %40 olarak bildirilmiştir. Rutin laboratuvarlarda penisilinaz varlığı fenotipik yöntemlerle (disk difüzyon, zon kenarı, nitrosefin testi) araştırılmakta, ancak özellikle alt tip ayrımı yapılamadığı için CzIE’yi öngörmede yetersiz kalmaktadır. Son yıllarda disk difüzyon temelli yeni testler geliştirilmiş olsa da daha geniş ölçekli çalışmalara gereksinim vardır. Sonuç olarak, MSSA enfeksiyonlarında gerek yan etki gerekse ulaşılabilir olması nedeniyle birincil seçenek olarak önerilen sefazolin kullanımında CzIE’nin klinik önemini netleştirmek için ileri araştırmalara gereksinim vardır.
Group 2a β-lactamases belong to Ambler class A and include narrow-spectrum penicillinases. Their main representative, PC1, hydrolyzes benzylpenicillin and derivatives, while showing limited activity against cephalosporins, carbapenems, and monobactams. Soon after penicillin entered clinical use in the 1940s, resistance rapidly emerged in staphylococci, mainly due to penicillinase production. By the 2000s, more than 80% of methicillin-susceptible Staphylococcus aureus (MSSA) isolates worldwide carried the blaZ penicillinase gene.
Two major resistance mechanisms exist in S. aureus: production of penicillinase encoded by blaZ, and altered penicillin-binding protein PBP2a encoded by mecA. At least four types (A–D) of blaZ have been identified; types A and C are most clinically relevant. These enzymes are linked to the “cefazolin inoculum effect” (CzIE), which may lead to treatment failures. A large Latin American study found type C most prevalent (37%), followed by type A, with an overall CzIE prevalence of 40%. Detection of penicillinase in routine labs relies on phenotypic methods such as disk diffusion, zone edge test, and nitrocefin assay. However, these approaches cannot determine blaZ subtypes and thus are insufficient to predict CzIE. Recently, disk diffusion–based assays have been developed to identify strains associated with inoculum effect, but validation with larger datasets is still required. In conclusion, although cefazolin remains a recommended first-line agent against MSSA infections due to its safety and accessibility, CzIE raises concerns about treatment reliability. Further clinical and laboratory studies are essential to clarify its true impact.
Referanslar
Bush K, Bradford PA. Epidemiology of β-Lactamase-Producing Pathogens. Clin. Microbiol Rev.2020;33(2):e00047-19.
Sangappa M, Thiagaran P. Methicillin resistant from Staphylococcus aureus: Resistance genes and their regulation. Int J Pharmacy and Pharmaceutical Sciences. 2012; 4(Suppl 1): 658-667.
Olsen JE, Christensen H, Aarestrup FM. Diversity and evolution of blaZ from Staphylococcus aureus and coagulase-negative staphylococci. JAC.2006;57:450–460.
Ferreira AM, Martins KB, da Silva VR, et al. Correlation of phenotypic tests with the presence of the blaZ gene for detection of β-lactamase. Brazil J Microbiol. 2017; 48(1): 159-166.
Shinwon Le, Ki Tae Kwon, Hye-In Kim, et al. Clinical implications of cefazolin inoculum effect and β-lactamase type on methicillin-susceptible Staphylococcus aureus bacteremia. Microb Drug Resist. 2014;20(6):568-74.
Lecomte R, Bourreau A, Deschanvres C, et al. Comparative outcomes of cefazolin versus antistaphylococcal penicillins in methicillin-susceptible Staphylococcus aureus infective endocarditis: a post hoc analysis of a prospective multicentre French cohort study. Clin Microbiol and Inf. 2021; 27:1015-102.
Carvajal LP, Rincon S, Echeverri AM, et al. Novel insights into the classification of Staphylococcal-Lactamases in relation to the cefazolin inoculum effect. Antimic Agents Chem. 2020;64(5):e02511-19.
Baptiste J, Maelys C, Pollani C, et al. β-Lactam inoculum effect in Methicillin-Susceptible Staphylococcus aureus infective endocarditis. JAMA Network Open. 2024;7(12):e2451353.
Wang SK, Gilchrist A, Loukitcheva A,et al. Prevalence of a cefazolin inoculum effect associated with blaZ gene types among Methicillin-Susceptible Staphylococcus aureus isolates from four major medical centers in Chicago. Antimic Agents Chem. 2018; 62(8):e00382-18.
Nannini EC, Stryjewski ME, Singh KV, et al. Inoculum effect with cefazolin among clinical isolates of Methicillin-Susceptible Staphylococcus aureus: Frequency and possible cause of cefazolin treatment failure. Antimic Agents Chem. 2009;53:3437-3441.
Takayama Y, Tanaka T, Oikawa K, Fukano N, Goto M, Takahashi T. Prevalence of blaZ gene and performance of phenotypic tests to detect penicillinase in Staphylococcus aureus isolates from Japan. Ann Lab Med 2018; 38:155-159
Cosgrove SE, Loren GM. The inoculum effect and Staphylococcus aureus infective endocarditis-time to Reconsider treatment? JAMA Network Open. 2024;7(12):e2451300.
George R, Lahra MM, Nguyen T, Gatus B. Disc test for detecting Staphylococcus aureus strains producing type A and type C β-Lactamases. Microbiology Spectrum. 2023;11(4): e0022023.
Ka-Fung Lo C, Sritharan A, Zhang J, et al. Clinical significance of cefazolin inoculum effect in serious MSSA infections: a systematic review. JAC Antimicrob Resist. 2024; 6(3):dlae069.https://doi.org/10.1093/jacamr/dlae069.
Referanslar
Bush K, Bradford PA. Epidemiology of β-Lactamase-Producing Pathogens. Clin. Microbiol Rev.2020;33(2):e00047-19.
Sangappa M, Thiagaran P. Methicillin resistant from Staphylococcus aureus: Resistance genes and their regulation. Int J Pharmacy and Pharmaceutical Sciences. 2012; 4(Suppl 1): 658-667.
Olsen JE, Christensen H, Aarestrup FM. Diversity and evolution of blaZ from Staphylococcus aureus and coagulase-negative staphylococci. JAC.2006;57:450–460.
Ferreira AM, Martins KB, da Silva VR, et al. Correlation of phenotypic tests with the presence of the blaZ gene for detection of β-lactamase. Brazil J Microbiol. 2017; 48(1): 159-166.
Shinwon Le, Ki Tae Kwon, Hye-In Kim, et al. Clinical implications of cefazolin inoculum effect and β-lactamase type on methicillin-susceptible Staphylococcus aureus bacteremia. Microb Drug Resist. 2014;20(6):568-74.
Lecomte R, Bourreau A, Deschanvres C, et al. Comparative outcomes of cefazolin versus antistaphylococcal penicillins in methicillin-susceptible Staphylococcus aureus infective endocarditis: a post hoc analysis of a prospective multicentre French cohort study. Clin Microbiol and Inf. 2021; 27:1015-102.
Carvajal LP, Rincon S, Echeverri AM, et al. Novel insights into the classification of Staphylococcal-Lactamases in relation to the cefazolin inoculum effect. Antimic Agents Chem. 2020;64(5):e02511-19.
Baptiste J, Maelys C, Pollani C, et al. β-Lactam inoculum effect in Methicillin-Susceptible Staphylococcus aureus infective endocarditis. JAMA Network Open. 2024;7(12):e2451353.
Wang SK, Gilchrist A, Loukitcheva A,et al. Prevalence of a cefazolin inoculum effect associated with blaZ gene types among Methicillin-Susceptible Staphylococcus aureus isolates from four major medical centers in Chicago. Antimic Agents Chem. 2018; 62(8):e00382-18.
Nannini EC, Stryjewski ME, Singh KV, et al. Inoculum effect with cefazolin among clinical isolates of Methicillin-Susceptible Staphylococcus aureus: Frequency and possible cause of cefazolin treatment failure. Antimic Agents Chem. 2009;53:3437-3441.
Takayama Y, Tanaka T, Oikawa K, Fukano N, Goto M, Takahashi T. Prevalence of blaZ gene and performance of phenotypic tests to detect penicillinase in Staphylococcus aureus isolates from Japan. Ann Lab Med 2018; 38:155-159
Cosgrove SE, Loren GM. The inoculum effect and Staphylococcus aureus infective endocarditis-time to Reconsider treatment? JAMA Network Open. 2024;7(12):e2451300.
George R, Lahra MM, Nguyen T, Gatus B. Disc test for detecting Staphylococcus aureus strains producing type A and type C β-Lactamases. Microbiology Spectrum. 2023;11(4): e0022023.
Ka-Fung Lo C, Sritharan A, Zhang J, et al. Clinical significance of cefazolin inoculum effect in serious MSSA infections: a systematic review. JAC Antimicrob Resist. 2024; 6(3):dlae069.https://doi.org/10.1093/jacamr/dlae069.
