Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Pfizer Ireland Pharmaceuticals, Operations Support Group, Ringaskiddy, County Cork, Ireland
Pharmacotherapeutic group: Antibacterials for systemic use, other cephalosporins and penems
ATC code: J01DI02
The active moiety after Zinforo administration is ceftaroline.
In vitro studies have shown that ceftaroline is bactericidal and able to inhibit bacterial cell wall synthesis in methicillin-resistant Staphylococcus aureus (MRSA) and penicillin non-susceptible Streptococcus pneumoniae (PNSP) due to its affinity for the altered penicillin-binding proteins (PBPs) found in these organisms. As a result, minimum inhibitory concentrations (MICs) of ceftaroline against a proportion of these organisms tested fall into the susceptible range (see Resistance section below).
Ceftaroline is not active against strains of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B metallo-beta-lactamases or class C (AmpC) cephalosporinases. Organisms that express these enzymes and which are therefore resistant to ceftaroline occur at very variable rates between countries and between healthcare facilities within countries. If ceftaroline is commenced before susceptibility test results are available then local information on the risk of encountering organisms that express these enzymes should be taken into consideration. Resistance may also be mediated by bacterial impermeability or drug efflux pump mechanisms. One or more of these mechanisms may co-exist in a single bacterial isolate.
In vitro studies have not demonstrated any antagonism between ceftaroline in combination with other commonly used antibacterial agents (e.g. amikacin, azithromycin, aztreonam, daptomycin, levofloxacin, linezolid, meropenem, tigecycline, and vancomycin).
The European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for susceptibility testing are presented below.
| Organisms | MIC breakpoints (mg/L) | |
|---|---|---|
| Susceptible (≤S) | Resistant (R>) | |
| Staphylococcus aureus | 11 | >22 |
| Streptococcus pneumoniae | 0.25 | 0.25 |
| Streptococcus Groups A, B, C, G | Note3 | Note3 |
| Haemophilus influenzae | 0.03 | 0.03 |
| Enterobacteriaceae | 0.5 | 0.5 |
1 Refers to dosing of adults or adolescents (from 12 years and 33 kg) with ceftaroline every 12 hours using 1-hour infusions (see section 4.2). Note that: There are no clinical trial data regarding the use of ceftaroline to
treat CAP due to S. aureus with ceftaroline MICs >1 mg/L
2 Refers to dosing of adults or adolescents (from 12 years and 33 kg) with ceftaroline every 8 hours using 2-hour infusions to treat cSSTI (see section 4.2). S. aureus with ceftaroline MICs ≥4 mg/L are rare. PK-PD analyses suggest that dosing of adults or adolescents (from 12 years and 33 kg) with ceftaroline every 8 hours using 2-hour infusions may treat cSSTI due to S. aureus for which the ceftaroline MIC is 4 mg/L.
3 Infer susceptibility from susceptibility to benzylpenicillin.
As with other beta-lactam antimicrobial agents, the percent time above the minimum inhibitory concentration (MIC) of the infecting organism over the dosing interval (%T > MIC) has been shown to be the parameter that best correlates with the efficacy of ceftaroline.
Efficacy has been demonstrated in clinical studies against the pathogens listed under each indication that were susceptible to ceftaroline in vitro.
Gram-positive micro-organisms:
Staphylococcus aureus (including methicillin-resistant strains)
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)
Streptococcus dysgalactiae
Gram-negative micro-organisms:
Escherichia coli
Klebsiella pneumoniae
Klebsiella oxytoca
Morganella morganii
No cases of CAP due to MRSA were enrolled into the studies. The available clinical data cannot substantiate efficacy against penicillin non-susceptible strains of S. pneumoniae.
Gram-positive micro-organisms:
Streptococcus pneumoniae
Staphylococcus aureus (methicillin-susceptible strains only)
Gram-negative micro-organisms:
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to ceftaroline in the absence of acquired mechanisms of resistance:
Gram-positive micro-organisms:
Peptostreptococcus spp.
Gram-negative micro-organisms:
Fusobacterium spp.
In vitro data indicate that the following species are not susceptible to ceftaroline:
Chlamydophila spp.
Legionella spp.
Mycoplasma spp.
Proteus spp.
Pseudomonas aeruginosa
The European Medicines Agency has deferred the obligation to submit the results of studies with Zinforo in the paediatric population aged birth to <2 months (see section 4.2 for information on paediatric use).
The Cmax and AUC of ceftaroline increase approximately in proportion to dose within the single dose range of 50 to 1000 mg. No appreciable accumulation of ceftaroline is observed following multiple intravenous infusions of 600 mg every 8 or 12 hours in healthy adults with CrCL >50 mL/min.
The plasma protein binding of ceftaroline is low (approximately 20%) and ceftaroline is not distributed into erythrocytes. The median steady-state volume of distribution of ceftaroline in healthy adult males following a single 600 mg intravenous dose of radiolabelled ceftaroline fosamil was 20.3 l, similar to the volume of extracellular fluid.
Ceftaroline fosamil (prodrug) is converted into the active ceftaroline in plasma by phosphatase enzymes and concentrations of the prodrug are measurable in plasma primarily during intravenous infusion. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite, ceftaroline M-1. The mean plasma ceftaroline M-1 to ceftaroline AUC ratio following a single 600 mg intravenous infusion of ceftaroline fosamil in healthy subjects is approximately 20-30%.
In pooled human liver microsomes, metabolic turnover was low for ceftaroline, indicating that ceftaroline is not metabolised by hepatic CYP450 enzymes.
Ceftaroline is primarily eliminated by the kidneys. Renal clearance of ceftaroline is approximately equal, or slightly lower than the glomerular filtration rate in the kidney, and in vitro transporter studies indicate that active secretion does not contribute to the renal elimination of ceftaroline.
The mean terminal elimination half-life of ceftaroline in healthy adults is approximately 2.5 hours.
Following the administration of a single 600 mg intravenous dose of radiolabelled ceftaroline fosamil to healthy male adults, approximately 88% of radioactivity was recovered in urine and 6% in faeces.
Dosage adjustments are required in adults, adolescents and children with CrCL ≤50 mL/min (see section 4.2).
There is insufficient information to recommend dosage adjustments in adolescents with ESRD aged from 12 to <18 years and with bodyweight <33 kg and in children with ESRD aged from 2 to <12 years. There is insufficient information to recommend dosage adjustments in children aged <2 years with moderate or severe renal impairment or ESRD.
The pharmacokinetics of ceftaroline in patients with hepatic impairment has not been established. As ceftaroline does not appear to undergo significant hepatic metabolism, the systemic clearance of ceftaroline is not expected to be significantly affected by hepatic impairment. Therefore, no dosage adjustment is recommended for patients with hepatic impairment.
Following administration of a single 600 mg intravenous dose of ceftaroline fosamil, the pharmacokinetics of ceftaroline were similar between healthy elderly subjects (≥65 years of age), and healthy young adult subjects (18-45 years of age). There was a 33% increase in AUC0-∞ in the elderly that was mainly attributable to age-related changes in renal function. Zinforo dose adjustment is not required in elderly patients with creatinine clearance above 50 mL/min.
Dose adjustments are required for children aged from 2 months to <12 years and for adolescents aged 12 to <18 years with bodyweight <33 kg (see section 4.2). The safety and efficacy of Zinforo in children aged birth to <2 months have not been established.
The kidney was the primary target organ of toxicity in both the monkey and rat. Histopathologic findings included pigment deposition and inflammation of the tubular epithelium. Renal changes were not reversible but were reduced in severity following a 4 week recovery period.
Convulsions have been observed at relatively high exposures during single and multi-dose studies in both the rat and monkey (≥7 times to the estimated ceftaroline Cmax level of a 600 mg twice a day).
Other important toxicologic findings noted in the rat and monkey included histopathologic changes in the bladder and spleen.
Ceftaroline fosamil and ceftaroline were clastogenic in an in vitro chromosomal aberration assay, however there was no evidence of mutagenic activity in an Ames test, mouse lymphoma and unscheduled DNA synthesis assay. Furthermore, in vivo micronucleus assays in rat and mouse were negative. Carcinogenicity studies have not been conducted.
Overall, no adverse effects on fertility or post-natal development were observed in the rat at up to 5 times the observed clinical exposure. When ceftaroline was administered during organogenesis, minor changes in foetal weight and delayed ossification of the interparietal bone were observed in the rat at exposures below that observed clinically. However, when ceftaroline was administered throughout pregnancy and lactation, there was no effect on pup weight or growth. Ceftaroline administration to pregnant rabbits resulted in an increased foetal incidence of angulated hyoid alae, a common skeletal variation in rabbit fetuses, at exposures similar to those observed clinically.
Intravenous bolus dosing of ceftaroline fosamil to suckling rats from post-natal day 7 to 20 was well tolerated at plasma exposures approximately 2-fold higher than those for paediatric patients. Renal cortical cysts were oberved in all groups, including controls, on PND50. The cysts involved a small portion of the kidney and ocurred in the absence of significant changes in either renal function or urinary parameters. Therefore, these findings were not considered to be adverse.
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