So what have I found out about Ceftaroline? How does it work? Why is it active against MRSA? Read on to discover the answers to these questions and many more about this new antibiotic…
Ceftaroline is a cephalosporin antibiotic that works by binding to penicillin binding proteins (PBPs) which interferes with cell wall synthesis. Ceftaroline has a high affinity for PBPs 1-4 as well as PBP2a; this is important because it is the production of PBP2a which makes Meticillin resistant Staphylococcus aureus (MRSA) resistant to other beta-lactam antibiotics. Ceftaroline has also been shown to be able to bind to all PBPs found in Streptococcus pneumoniae as well as the PBPs in many Gram-negative bacteria. As a result of this ability to bind to PBP2a Ceftaroline has a broad spectrum of activity against bacteria, including those normally thought to be resistant to beta-lactams.
Like other cephalosporins, the main marker of activity is being able to maintain a concentration greater than the minimum inhibitory concentration (MIC) for the particular bacterium. Having a peak concentration of approximately 20mg/L and the half-life of approximately 2 ½ hours in steady state, means that for blood stream infections bacteria need to have an MIC of approximately ≤1mg/L for Ceftaroline to be active.
What is the spectrum of activity of Ceftaroline?
Ceftaroline is ACTIVE against:
- S. aureus including MRSA, Vancomycin resistant S. aureus (VRSA)
- Coagulase negative staphylococci including S. epidermidis, S. lugdenensis, S. hominis and S. haemolyticus
- Beta-haemolytic streptococci groups A, B, C, F and G
- S. pneumoniae including Ceftriaxone and Cefotaxime resistant strains
- Haemophilus influenzae
- Moraxella catarrhalis
- Enterobacteriaceae such as E. coli and Klebsiella spp. except ESBL or Amp C positive strains
Of note Ceftaroline is NOT ACTIVE against:
- ESBL or AmpC positive Enterobacteriaceae including Enterobacter cloacae, Serratia marcesans, Citrobacter freundii
- Pseudomonas aeruginosa
- Stenotrophomonas maltophilia
- Bacteroides fragilis
- Acinetobacter baumanii
Ceftaroline resistance is thought to occur infrequently in Gram-positive bacteria as in vitro attempts to induce resistance have been unable to create resistant bacteria, but in vivo where there is the potential for bacteria to share genes via mobile genetic elements such as plasmids and transposons this may be more apparent.
There is some limited in vitro data that suggests that Ceftaroline PLUS Amikacin might be synergistic against P. aeruginosa but there is little clinical evidence to back this up. I guess if your back was against the wall and you had no other choices you might give this kind of thing a go but I can’t imagine a scenario where this is likely.
It has been proposed that Ceftaroline should be classified as a 5th generation cephalosporin but I think it should really be considered unique. By convention 5th generation cephalosporins should have excellent Gram-negative activity and modest or no Gram-positive activity whereas this is clearly not the case with Ceftaroline; it is also not 1st generation as it has activity against MRSA. It does not fit the normal generation scheme so let’s just leave it on its own; it is unique.
How is Ceftaroline administered?
Ceftaroline is only available as an intravenous infusion, although it can also be given intramuscularly if necessary i.e. given IM to avoid missing doses due to loss of IV access. The normal dose is 600mg BD.
Ceftaroline is excreted via the kidneys, with 65% of the drug remaining active in the urinary tract making it possible to treat urinary tract infections with this drug if necessary. However the renal excretion means that the drug needs dose adjusting in renal failure as well as haemodialysis.
Does Ceftaroline interact with other medications?
Ceftaroline is not metabolised by the cytochrome P450 pathway in the liver and therefore the potential for interactions with other medications is unlikely, however there are no formal studies published addressing this.
What are the side effects of Ceftaroline?
The side-effects from Ceftaroline are similar to other cephalosporins, the most common being:
- Diarrhoea (4.2%)
- Headache (3.4%)
- Nausea (2.3%)
- Rash (1.9%)
Across all of the Phase 3 studies for Ceftaroline there were only 2 cases of Clostridium difficile associated disease (CDAD) amongst 1305 patients exposed to the antibiotic. This was comparable to the comparator drugs in those studies all of which except Ceftriaxone are considered low risk antibiotics. It would seem that Ceftaroline is not a high risk antibiotic for CDAD but it is NOT NO RISK for CDAD.
What are the clinical uses of Ceftaroline?
Ceftaroline is licensed for use in community acquired pneumonia (CAP) and skin and soft tissue infection (SSTI) in both the UK and USA.
In randomised double blinded studies for SSTIs, whether they were caused by MRSA or Meticillin Sensitive Staphylococcus aureus (MSSA), Ceftaroline was shown to be non-inferior to Vancomycin PLUS Aztreonam; in fact the cure rates were better for Ceftaroline (96.7% versus 88.9%). HOWEVER, I have a bit of a problem with this study and that is that Vancomycin PLUS Aztreonam is not the gold-standard therapy for MSSA infections, Flucloxacillin is. Therefore Ceftaroline should be compared to this treatment not Vancomycin PLUS Aztreonam. In fact Aztreonam is not necessary for almost all SSTIs because they are usually caused by Gram-positive bacteria and Aztreonam has no useful Gram-positive activity. Comparing Ceftaroline to Vancomycin MIGHT be acceptable for MRSA infections but that wasn’t the case in the studies which have led to it getting a license. If Vancomycin is in fact inferior to Flucloxacillin (and in my experience it usually is) then according to the studies Ceftaroline (which appears equivalent to Vancomycin) might also be inferior to Flucloxacillin. There really needs to be a direct comparison between Ceftaroline and Flucloxacillin before a decision is made whether to use Ceftaroline first line. Until then I would suggest Flucloxacillin is still the best treatment for SSTI.
The clinical trials evaluating Ceftaroline for CAP compared it to Ceftriaxone and showed there was a better clinical outcome with Ceftaroline (86.6% versus 78.2%). HOWEVER, I also have a slight problem with these studies in that Ceftriaxone is not normal first line therapy for CAP. My problem with this though is less than with the SSTI studies because Ceftriaxone could be first line therapy for CAP in that it can be used to treat the common bacterial causes of CAP (e.g. S. pneumoniae and H. influenzae) but in more difficult to reach sites (e.g. cerebrospinal fluid). The beta-lactams more commonly used to treat CAP e.g. Amoxicillin, Co-amoxiclav, Cefuroxime, don’t penetrate some areas. I just think if you are going to look at efficacy and safety you should compare to the currently used gold-standard treatment not some other randomly selected antibiotic. That is unless the manufacturers don’t believe their new antibiotic is actually up to matching or improving the outcome!?!
Is Ceftaroline really a new antibiotic?
OK so Ceftaroline isn’t really a new antibiotic, but its activity against MRSA means it should be considered as “new” even if it is still a cephalosporin. So when am I likely to use it in my patients? Probably for SSTI caused by MRSA where I don’t want to use a glycopeptide (e.g. Vancomycin or Teicoplanin) and where I am worried about side-effects or drug interactions due to drugs like Daptomycin or Linezolid. I doubt I will ever use it for CAP as even in those rare cases of MRSA pneumonia, Linezolid is probably a better choice.
Over time, however, it might become my go to antibiotic for MRSA SSTIs but probably only if and when it becomes cheaper (Ceftaroline = £75.00 per day compared to Teicoplanin £7.32 per day… which over a 10 day course would be £675.00 more expensive… ouch!).