A Drug Monograph; Cefiderocol

Abstract

Increasing antimicrobial resistance day by day necessitates the search for new antimicrobials. Carbapenem resistance, especially in gram-negative bacteria, has reached alarming levels and has become a global public health problem due to the lack of safe alternative treatment options. Cefiderocol is a novel injectable siderophore cephalosporin that hijacks the bacterial iron transport machinery to facilitate cell entry and achieve high periplasmic concentrations. The cephalosporin moiety is the active antimicrobial component, structurally resembling a hybrid between ceftazidime and cefepime. Like other β-lactam agents, the principal bactericidal activity of cefiderocol occurs via inhibition of bacterial cell wall synthesis by binding of penicillin-binding proteins and inhibiting peptidoglycan synthesis, leading to cell death. Cefiderocol has been shown to be stable against hydrolysis by both serine and metallo-ß-lactamases in four Ambler classes, classes A, B, C, and D. Also, efflux pump-mediated resistance and porin mutations have limited effects on cefiderocol. It has broad in vitro activity against gram-negative bacteria, including multidrug-resistant organisms such as carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia and Burkholderia cepacia. It has proven efficacy in the treatment of complicated cases such as complex urinary tract infections, including pyelonephritis, complex intra-abdominal infections, hospital-acquired bacterial pneumonia therapy, and ventilator-associated bacterial pneumonia. It was approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections and nosocomial pneumonia, ventilator-associated bacterial pneumonia. The recommended dose of cefiderecol for complicated urinary tract infections is 2 grams every 8 hours for 7-14 days, 2 grams every 8 hours for 5-14 days for complicated intra-abdominal infections, and it is recommended to be administered as a 3-hour infusion. Cefiderocol is primarily renally excreted unchanged and clearance correlates with creatinine clearance. Dosage adjustment is thus required for both augmented renal clearance and in patients with moderate to severe renal impairment. In vitro and in vivo pharmacodynamic studies have reported that as with other cephalosporins the pharmacodynamic index that best predicts clinical outcome is the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (%fT> MIC). Cefiderocol appears to be well tolerated with side-effect profiles similar to other cephalosporins. Cefiderocol displays favorable pharmacokinetic/pharmacodynamic properties and an acceptable safety profile, suggesting that cefiderocol may be a viable option for treating infections caused by bacteria resistant to other antibiotics.

Keywords

• antibiotic resistance
• carbapenem
• cefiderocol
• cephalosporin

Bir İlaç Monografı; Sefiderokol

Abstract

Gün geçtikçe artan antibimikrobiyal direnç yeni antimikrobiyaller arayışını zorunlu kılmaktadır. Özellikle gram negatif bakterilerdeki karbapenem direnci endişe verici seviyelere ulaşmıştır ve güvenli alternatif tedavi seçeneklerinin olmaması nedeniyle küresel bir halk sağlığı sorunu haline gelmiştir. Sefiderokol, hücre girişini kolaylaştırmak ve yüksek periplazmik konsantrasyonlar elde etmek için bakteriyel demir transport mekanizmasını kullanan yeni bir siderofor sefalosporindir. Sefalosporin parçası, yapısal olarak seftazidim ve sefepim arasında hibrite benzeyen aktif antimikrobiyal bileşendir. Temel bakterisidal aktivitesi diğer β-laktam antibiyotikler gibi penisilin bağlayan proteinlere bağlanarak peptidoglikan sentezinin dolayısıyla hücre duvarının inhibisyonu ve hücre ölümüne yol açması ile gerçekleşir. Sefiderokolün sınıf A, B, C ve D olmak üzere dört Ambler sınıfında hem serin hem de metallo-ß-laktamazlar tarafından hidrolize karşı kararlı olduğu gösterilmiştir. Aynı zamanda effluks pompası aracılı direnç ve porin mutasyonları sefiderokol üzerinde sınırlı etkiye sahiptir. Karbapenem dirençli Enterobacterales, karbapenem dirençli Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia ve Burkholderia cepacia gibi çoklu ilaca dirençli organizmalar dahil olmak üzere gram negatif bakterilere karşı geniş in vitro etkinliğe sahiptir. Piyelonefrit dahil komplike idrar yolu enfeksiyonları, komplike intraabdominal enfeksiyonlar, hastane kökenli bakteriyel pnömoni ve ventilatör ilişkili bakteriyel pnömoni gibi komplike vakaların tedavisinde etkinliği kanıtlanmıştır. ABD Gıda ve İlaç İdaresi tarafından komplike üriner sistem enfeksiyonları ve nozokomiyal pnömoni, ventilatör ilişkili bakteriyel pnömoninin tedavisi için onaylanmıştır. Komplike üriner sistem enfeksiyonları için önerilen sefiderekol dozu 7- 14 gün boyunca her 8 saatte bir 2 gram, komplike intraabdominal enfeksiyonlar için, 5- 14 gün boyunca her 8 saatte bir 2 gramdır ve 3 saatlik infüzyon olarak uygulanması önerilir. Sefiderokol böbrekler tarafından değişmeden atılır ve klerens, kreatinin klerensi ile ilişkilidir. Bu nedenle hem artmış renal klerens için hem de orta ve şiddetli böbrek yetmezliği olan hastalarda doz ayarlaması gereklidir. In vitro ve in vivo farmakodinamik çalışmalar, diğer sefalosporinlerde olduğu gibi, klinik sonucu en iyi tahmin eden farmakodinamik indeksin, serbest ilaç konsantrasyonlarının minimum inhibitör konsantrasyonu aştığı zamanın yüzdesi olduğunu bildirmiştir. Diğer sefalosporinlere benzer yan etki profilleri olmakla beraber iyi tolere ediliyor görünmektedir. Sefiderokol uygun farmakokinetik/farmakodinamik özellikler ve kabul edilebilir bir güvenlik profili sergiler ve bu durum sefiderekolün diğer antibiyotiklere dirençli bakterilerin neden olduğu enfeksiyonların tedavisinde uygun bir seçenek olabileceğini düşündürmektedir.

Keywords

• Antibiyotik direnci
• karbapenem
• sefiderokol
• sefalosporin

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