Ceftaroline

Abstract

Ceftaroline is a broad-spectrum cephalosporin currently under clinical investigation for the treatment of complicated skin and skin-structure infections (cSSSI), including those caused by meticillin-resistant Staphylococcus aureus (MRSA), and community-acquired pneumonia (CAP). Ceftaroline has the ability to bind to penicillin-binding protein (PBP)2a, an MRSA-specific PBP that has low affinity for most other beta-lactam antibacterials. The high binding affinity of ceftaroline to PBP2a (median inhibitory concentration 0.90 microg/mL) correlates well with its low minimum inhibitory concentration for MRSA. Ceftaroline is active in vitro against Gram-positive cocci, including MRSA, meticillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococcus faecalis (not E. faecium). The broad-spectrum activity of ceftaroline includes many Gram-negative pathogens but does not extend to extended-spectrum beta-lactamase-producing or AmpC-derepressed Enterobacteriaceae or most nonfermentative Gram-negative bacilli. Ceftaroline demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. Limited data show that ceftaroline has a low propensity to select for resistant subpopulations. Ceftaroline fosamil (prodrug) is rapidly converted by plasma phosphatases to active ceftaroline. For multiple intravenous doses of 600 mg given over 1 h every 12 hours for 14 days, the maximum plasma concentration was 19.0 microg/mL and 21.0 microg/mL for first and last dose, respectively. Ceftaroline has a volume of distribution of 0.37 L/kg (28.3 L), low protein binding (<20%) and a serum half-life of 2.6 hours. No drug accumulation occurs with multiple doses and elimination occurs primarily through renal excretion (49.6%). Based on Monte Carlo simulations, dosage adjustment is recommended for patients with moderate renal impairment (creatinine clearance 30-50 mL/min); no adjustment is needed for mild renal impairment. Currently, limited clinical trial data are available for ceftaroline. A phase II study randomized 100 patients with cSSSI to intravenous ceftaroline 600 mg every 12 hours or intravenous vancomycin 1 g every 12 hours with or without intravenous aztreonam 1 g every 8 hours (standard therapy) for 7-14 days. Clinical cure rates were 96.7% for ceftaroline compared with 88.9% for standard therapy. Adverse events were similar between groups and generally mild in nature. In a phase III trial, 702 patients with cSSSI were randomized to ceftaroline 600 mg or vancomycin 1 g plus aztreonam 1 g, each administered intravenously every 12 hours for 5-14 days. Ceftaroline was noninferior to vancomycin plus aztreonam in treating cSSSI caused by both Gram-positive and -negative pathogens. Adverse event rates were similar between groups. Ceftaroline is well tolerated, which is consistent with the good safety and tolerability profile of the cephalosporin class. In summary, ceftaroline is a promising treatment for cSSSI and CAP, and has potenti...

Targeting Antibiotic Resistance

“…Indeed, allosteric interactions are required to trigger a conformational change that opens the active site. Following these findings, three so‐called “fifth‐generation” cephalosporins, namely ceftaroline,144 ceftobiprole,145 and ceftolozane,146 were developed by following the currently known SAR (Figure 30), and these show activity against MRSA. …”

“…As seen in Figure 31, the western half remains mostly unchanged, with the 1,2,4‐thiadiazole and oxime moieties still present for Gram‐negative penetration and β‐lactamase resistance, respectively 144. Once bound, ceftaroline has been shown to undergo hydrolysis at a very slow rate 144. The phosphono group in the prodrug ceftaroline fosamil is used to increase water solubility and is rapidly cleaved in the plasma to deliver the active drug ceftaroline 147.…”

Resistencia a antibióticos de última línea en cocos Gram positivos: la era posterior a la vancomicina

“…La ceftarolina pertenece a una nueva clase de cefalosporinas con actividad contra SARM que algunos denominan 'cefalosporinas de quinta generación' (132) y que fue aprobada por la FDA para el tratamiento de adultos con infecciones complicadas de piel y tejidos blandos adquiridas en la comunidad (133,134). Su espectro de acción es muy amplio e incluye SARM, S. aureus de sensibilidad intermedia a la vancomicina, S. epidermidis resistente y sensible a la meticilina y S. pneumoniae con sensibilidad reducida a penicilina, eritromicina, amoxicicilina, fluoroquinolonas y cefotaxima (135).…”

“…En cuanto a los enterococos, la ceftarolina presenta actividad in vitro contra E. faecalis resistente y sensible a la vancomicina, pero no así contra E. faecium, (133,135). Su mecanismo de acción es similar al de otros betalactámicos, pues interfiere en la síntesis de la pared celular mediante la unión a las proteínas de unión a penicilina (PBP) (132).…”

“…A la fecha no se ha reportado resistencia a la ceftarolina en aislamientos clínicos, y distintas publicaciones han demostrado que la CIM 50 y la CIM 90 para SARM es de 0,5 y 1 µg/ml, respectivamente, valores que se repiten en S. pneumoniae sensible a la penicilina (136). Aunque sigue siendo activa, la ceftarolina en E. faecalis presenta CIM más altas, con una CIM 50 de 2 µg/ml y una CIM 90 de 4 µg/ml (133,135). Algunos estudios in vitro de selección de cepas resistentes, incluidas cepas de SARM-AC, S. aureus con heterorresistencia a la vancomicina, S. aureus sensible a la meticilina y S. pneumoniae resistente a la penicilina, no detectaron altos niveles de resistencia, lo que sugiere que la probabilidad de la emergencia de resistencia in vivo frente a esta nueva cefalosporina es baja (132,137,138).…”