Giancola Stephanie E, Mahoney Monica V, Bias Tiffany E, Hirsch Elizabeth B
Department of Pharmacy, St Mary's Medical Center, Huntington, WV, USA.
Beth Israel Deaconess Medical Center, Boston, MA, USA.
Ther Clin Risk Manag. 2016 May 19;12:787-97. doi: 10.2147/TCRM.S83844. eCollection 2016.
The rise in resistant Gram-negative pathogens continues to challenge clinicians treating infections. These resistant infections have inspired the development of new antimicrobial agents, including ceftolozane-tazobactam, a novel β-lactam/β-lactamase inhibitor combination approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) in combination with metronidazole. Ceftolozane exhibits bactericidal activity by inhibiting penicillin-binding proteins (PBPs), with high affinity for PBP1b, PBP1c, and PBP3. The addition of tazobactam protects ceftolozane from hydrolysis by irreversibly binding to some β-lactamase enzymes. Ceftolozane-tazobactam is active against a wide range of Gram-negative pathogens, including extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa, several streptococcal species, and Bacteroides fragilis. When anaerobic coverage is needed, it should be used in combination with metronidazole. Ceftolozane demonstrates linear pharmacokinetics, low protein binding, and minimal accumulation with repeated dosing. The major pharmacokinetic/pharmacodynamic index for ceftolozane is the percentage of the dosing interval in which the plasma free drug concentration remains higher than the minimum inhibitory concentration (%T.MIC). Phase III clinical trials for the treatment of cUTIs and cIAIs have been completed, showing that it is an effective and safe alternative for the treatment of these infections. The approved dose for cUTIs and cIAIs is 1.5 g (1 g ceftolozane and 500 mg tazobactam) infused over 1 hour every 8 hours. A higher 3 g dose is currently in Phase III trials for the treatment of ventilated nosocomial pneumonia. Dosage adjustments are necessary for patients with moderate-to-severe renal impairment. Current data suggest that ceftolozane-tazobactam is a promising carbapenem-sparing alternative agent for the treatment of cUTIs and cIAIs, including those caused by ESBL-producing Enterobacteriaceae and MDR P. aeruginosa.
革兰氏阴性耐药病原体的增加继续给治疗感染的临床医生带来挑战。这些耐药感染促使了新型抗菌药物的研发，包括头孢洛扎/他唑巴坦，这是一种新型的β-内酰胺/β-内酰胺酶抑制剂组合，已被美国食品药品监督管理局批准与甲硝唑联合用于治疗复杂性尿路感染（cUTIs）和复杂性腹腔内感染（cIAIs）。头孢洛扎通过抑制青霉素结合蛋白（PBPs）发挥杀菌活性，对PBP1b、PBP1c和PBP3具有高亲和力。添加他唑巴坦可通过与某些β-内酰胺酶不可逆结合来保护头孢洛扎不被水解。头孢洛扎/他唑巴坦对多种革兰氏阴性病原体具有活性，包括产超广谱β-内酰胺酶（ESBL）的肠杆菌科细菌和多重耐药（MDR）铜绿假单胞菌、几种链球菌属以及脆弱拟杆菌。当需要厌氧菌覆盖时，应与甲硝唑联合使用。头孢洛扎表现出线性药代动力学、低蛋白结合率且重复给药时蓄积最小。头孢洛扎的主要药代动力学/药效学指标是血浆游离药物浓度保持高于最低抑菌浓度的给药间隔百分比（%T.MIC）。治疗cUTIs和cIAIs的III期临床试验已经完成，表明它是治疗这些感染的一种有效且安全的替代药物。cUTIs和cIAIs的批准剂量为每8小时1次，每次1.5 g（1 g头孢洛扎和500 mg他唑巴坦），静脉输注1小时。目前更高剂量的3 g正在进行治疗呼吸机相关性医院获得性肺炎的III期试验。中重度肾功能损害患者需要调整剂量。目前的数据表明，头孢洛扎/他唑巴坦是一种有前景的碳青霉烯类药物节省替代药物，可用于治疗cUTIs和cIAIs，包括由产ESBL肠杆菌科细菌和MDR铜绿假单胞菌引起的感染。
