Antibiotic resistance is a major threat to public health. This isn’t just my opinion but also that of Dame Sally Davies, the Chief Medical Officer for England, as well as the World Health Organisation and other numerous national and international groups. It is not only the treatment of infections that will become impossible but perhaps an even greater threat is that surgery will no longer be possible without an unacceptable risk that the patient will die from a postoperative infection; who would want a surgeon to operate on their bowel without the availability of antibiotics to stop bowel bacteria causing peritonitis afterwards?
The biggest antibiotic resistance threats at present are the Gram-negative bacteria such as enterobacteriaceae (E. coli, Klebsiella spp., Enterobacter cloacae, etc.), Pseudomonas spp. and Acinetobacter spp. These are increasingly resistant to what have traditionally been considered “last line” antibiotics such as Piptazobactam, Meropenem and more recently Colistin. Bacteria become resistant through numerous methods but most commonly is the production of enzymes and efflux pumps.
So what is the solution? We produce new antibiotics which the bacteria have not yet developed a method of survival against. Yet drug companies don’t appear to be producing these new classes of antibiotics. So what are the drug companies actually doing? Some are either recombining old antibiotics into “new packages” or modifying old antibiotics to try and offer something that “looks new”. I suspect this is done because it is a much quicker and cheaper way to bring a “new” anti-infective drug to market but does this “lick of new paint” actually offer a new approach?
So what is the solution? We produce new antibiotics which the bacteria have not yet developed a method of survival against. Yet drug companies don’t appear to be producing these new classes of antibiotics. So what are the drug companies actually doing? Some are either recombining old antibiotics into “new packages” or modifying old antibiotics to try and offer something that “looks new”. I suspect this is done because it is a much quicker and cheaper way to bring a “new” anti-infective drug to market but does this “lick of new paint” actually offer a new approach?
These recombination antibiotics are usually a combination of an existing beta-lactam with a beta-lactamase inhibitor.
Examples of this include Ceftolozane-tazobactam, Ceftazidime-avibactam, Meropenem-vaborbactam, Imipenem-relebactam and Aztreonam-avibactam.
Whereas new versions of old antibiotics that aren’t beta-lactams include Eravacycline, Plazomicin and Cefiderocol.
The table below shows where each “new” antibiotic has activity against the bacteria resistant to the current widely used antibiotics (green=active, amber=partial/unreliable activity, red=inactive).
Examples of this include Ceftolozane-tazobactam, Ceftazidime-avibactam, Meropenem-vaborbactam, Imipenem-relebactam and Aztreonam-avibactam.
Whereas new versions of old antibiotics that aren’t beta-lactams include Eravacycline, Plazomicin and Cefiderocol.
The table below shows where each “new” antibiotic has activity against the bacteria resistant to the current widely used antibiotics (green=active, amber=partial/unreliable activity, red=inactive).
Click for larger image
Beta-lactamase inhibitor combinations
The difference in activity of the various inhibitor combinations is either due to the activity of the original parent antibiotic or the ability of the inhibitor to block the mechanism of resistance. As one might expect, the main role of these beta-lactamase inhibitor combinations is in the treatment of bacteria producing beta-lactamases.
Ceftolozane-tazobactam has shown activity against most ESBL positive bacteria as well as antibiotic-resistant Pseudomonas spp. in vitro. Clinical trials of this new combination are limited and I am a bit sceptical about some of the claims. This combination isn’t really that different from the commonly used Piptazobactam. The parent antibiotic Ceftolozane is not active against ESBL and AmpC producing bacteria in its own right and Piptazobactam is unreliable in vivo, against ESBL and AmpC positive bacteria. It has no activity against the carbapenemase (CPE) producing bacteria or Acinetobacter spp. and therefore I think it is of limited value.
Ceftazidime-avibactam has activity against a number of beta-lactamase producing bacteria including ESBL, AmpC and some carbapenemases such as KPC and OXA-48. This makes it useful for treating infections with resistant bacteria where these mechanisms of resistance have been confirmed. Disappointingly there is no activity against NDM and therefore it is unlikely that this antibiotic would be used first line for CPE producing bacteria until the mechanism is known. This may take days for the laboratory to confirm. It’s also not much use against antibiotic-resistant Pseudomonas spp. or Acinetobacter spp.
Unsurprisingly Meropenem-vaborbactam is active against ESBL and AmpC producing bacteria because Meropenem itself is the treatment of choice in these situations as it is not broken down by these enzymes. Vaborbactam is also able to block the KPC enzyme but does not have any activity against the other CPEs. In the same way as Ceftazidime-avibactam, it is unlikely Meropenem-vaborbactam as a combination will be used unless the bacterium is definitely known to be a KPC. Again activity against antibiotic-resistant Pseudomonas spp. and Acinetobacter spp. is limited.
Imipenem-relebactam is pretty much the same as Meropenem-vaborbactam and for the same reasons; Imipenem alone is active against ESBL and AmpC. The only real advantage is that Imipenem-relebactam remains active against antibiotic-resistant Pseudomonas spp. as Imipenem is not a substrate (a substance on which an enzyme acts) for the efflux pumps and is therefore not removed from the bacterium by this method.
Aztreonam-avibactam is similar to Ceftazidime-avibactam because the avibactam provides similar protection to the parent antibiotic, Aztreonam, as it does for Ceftazidime. As a result Aztreonam-avibactam is active against ESBL, AmpC, KPC and OXA-48 producing bacteria. The main difference however is that Aztreonam-avibactam is also active against NDM because the parent antibiotic, Aztreonam, is not degraded by this enzyme. Sadly it is not much use against antibiotic-resistant Pseudomonas spp. and Acinetobacter spp. but then I suppose you can’t have everything. I can see that it would be the empirical 1st choice treatment for an infection caused by a CPE producing enterobacteriaceae.
So what about the new versions of old antibiotics?
Eravacycline is a fluorocycline antibiotic, a modified tetracycline, similar to the glycylcycline Tigecycline. It is active in vitro, against enterobacteriaceae producing beta-lactamases as well as Acinetobacter spp. This is not really a surprise because it is not a beta-lactam (hence the beta-lactamase enzymes don’t target it) and Tigecycline, its closest relative, is also often active against Acinetobacter spp. It is hard to see what this antibiotic brings to the table that isn’t already there in the form of Tigecycline. It is currently still in development and may not make it to market as in the Phase III trials it was shown to be inferior to some current antibiotics in the treatment of UTIs such as Levofloxacin. This may be due to problems with penetration in to the urinary tract or because, like other tetracyclines, Eravacycline is bacteriostatic not bactericidal.
Plazomicin is a new synthetic aminoglycoside like Gentamicin, Amikacin and Tobramycin (I know Tobramycin is not synthetic but it is an aminoglycoside!). Like Amikacin it has good activity against many of the enterobacteriaceae but it seems that many of the bacteria that have acquired NDM have also acquired resistance to Plazomicin. It is currently in phase III clinical trials but it is likely to have a similar use to some of the other currently available aminoglycosides such as Amikacin.
Cefiderocol is still in the very early stages of development so don’t go rushing to your pharmacy just yet. It has a siderophore which allows it to chelate iron and make use of iron-uptake mechanisms into bacterial cells leading to high intracellular levels. Cefiderocol acts on Penicillin Binding Protein 3 (PBP3) in the same way as Ceftazidime but unlike Ceftazidime it is not broken down by ESBL, AmpC or CPE enzymes. It has also shown excellent activity against antibiotic-resistant Pseudomonas spp. and Acinetobacter spp. in vitro. The only real drawback with Cefiderocol at the moment is that it has no activity against Gram-positive or anaerobic bacteria, but this can easily be overcome in empirical regimens by using it in combination with other antibiotics such as glycopeptides (Teicoplanin and Vancomycin) and Metronidazole.
It is always exciting to see new drugs come through with the company’s literature offering “the answer” in a vibrant new tablet. But on closer examination things still look fairly uncertain at the moment in the treatment of antibiotic-resistant Gram-negative bacteria. All of the possible “new” agents have drawbacks. Although in my opinion Ceftazidime-avibactam, Aztreonam-avibactam and Cefiderocol show some promise and may well become antibiotics I use more frequently in the future.
The scenarios I can see me using these are:
Unfortunately the only one of these currently available on a routine basis is Ceftazidime-avibactam so my choices are still quite limited at present, but the others are on the horizon. Maybe it’s time to buy some shares… just be careful of the conflict of interest!
The difference in activity of the various inhibitor combinations is either due to the activity of the original parent antibiotic or the ability of the inhibitor to block the mechanism of resistance. As one might expect, the main role of these beta-lactamase inhibitor combinations is in the treatment of bacteria producing beta-lactamases.
Ceftolozane-tazobactam has shown activity against most ESBL positive bacteria as well as antibiotic-resistant Pseudomonas spp. in vitro. Clinical trials of this new combination are limited and I am a bit sceptical about some of the claims. This combination isn’t really that different from the commonly used Piptazobactam. The parent antibiotic Ceftolozane is not active against ESBL and AmpC producing bacteria in its own right and Piptazobactam is unreliable in vivo, against ESBL and AmpC positive bacteria. It has no activity against the carbapenemase (CPE) producing bacteria or Acinetobacter spp. and therefore I think it is of limited value.
Ceftazidime-avibactam has activity against a number of beta-lactamase producing bacteria including ESBL, AmpC and some carbapenemases such as KPC and OXA-48. This makes it useful for treating infections with resistant bacteria where these mechanisms of resistance have been confirmed. Disappointingly there is no activity against NDM and therefore it is unlikely that this antibiotic would be used first line for CPE producing bacteria until the mechanism is known. This may take days for the laboratory to confirm. It’s also not much use against antibiotic-resistant Pseudomonas spp. or Acinetobacter spp.
Unsurprisingly Meropenem-vaborbactam is active against ESBL and AmpC producing bacteria because Meropenem itself is the treatment of choice in these situations as it is not broken down by these enzymes. Vaborbactam is also able to block the KPC enzyme but does not have any activity against the other CPEs. In the same way as Ceftazidime-avibactam, it is unlikely Meropenem-vaborbactam as a combination will be used unless the bacterium is definitely known to be a KPC. Again activity against antibiotic-resistant Pseudomonas spp. and Acinetobacter spp. is limited.
Imipenem-relebactam is pretty much the same as Meropenem-vaborbactam and for the same reasons; Imipenem alone is active against ESBL and AmpC. The only real advantage is that Imipenem-relebactam remains active against antibiotic-resistant Pseudomonas spp. as Imipenem is not a substrate (a substance on which an enzyme acts) for the efflux pumps and is therefore not removed from the bacterium by this method.
Aztreonam-avibactam is similar to Ceftazidime-avibactam because the avibactam provides similar protection to the parent antibiotic, Aztreonam, as it does for Ceftazidime. As a result Aztreonam-avibactam is active against ESBL, AmpC, KPC and OXA-48 producing bacteria. The main difference however is that Aztreonam-avibactam is also active against NDM because the parent antibiotic, Aztreonam, is not degraded by this enzyme. Sadly it is not much use against antibiotic-resistant Pseudomonas spp. and Acinetobacter spp. but then I suppose you can’t have everything. I can see that it would be the empirical 1st choice treatment for an infection caused by a CPE producing enterobacteriaceae.
So what about the new versions of old antibiotics?
Eravacycline is a fluorocycline antibiotic, a modified tetracycline, similar to the glycylcycline Tigecycline. It is active in vitro, against enterobacteriaceae producing beta-lactamases as well as Acinetobacter spp. This is not really a surprise because it is not a beta-lactam (hence the beta-lactamase enzymes don’t target it) and Tigecycline, its closest relative, is also often active against Acinetobacter spp. It is hard to see what this antibiotic brings to the table that isn’t already there in the form of Tigecycline. It is currently still in development and may not make it to market as in the Phase III trials it was shown to be inferior to some current antibiotics in the treatment of UTIs such as Levofloxacin. This may be due to problems with penetration in to the urinary tract or because, like other tetracyclines, Eravacycline is bacteriostatic not bactericidal.
Plazomicin is a new synthetic aminoglycoside like Gentamicin, Amikacin and Tobramycin (I know Tobramycin is not synthetic but it is an aminoglycoside!). Like Amikacin it has good activity against many of the enterobacteriaceae but it seems that many of the bacteria that have acquired NDM have also acquired resistance to Plazomicin. It is currently in phase III clinical trials but it is likely to have a similar use to some of the other currently available aminoglycosides such as Amikacin.
Cefiderocol is still in the very early stages of development so don’t go rushing to your pharmacy just yet. It has a siderophore which allows it to chelate iron and make use of iron-uptake mechanisms into bacterial cells leading to high intracellular levels. Cefiderocol acts on Penicillin Binding Protein 3 (PBP3) in the same way as Ceftazidime but unlike Ceftazidime it is not broken down by ESBL, AmpC or CPE enzymes. It has also shown excellent activity against antibiotic-resistant Pseudomonas spp. and Acinetobacter spp. in vitro. The only real drawback with Cefiderocol at the moment is that it has no activity against Gram-positive or anaerobic bacteria, but this can easily be overcome in empirical regimens by using it in combination with other antibiotics such as glycopeptides (Teicoplanin and Vancomycin) and Metronidazole.
It is always exciting to see new drugs come through with the company’s literature offering “the answer” in a vibrant new tablet. But on closer examination things still look fairly uncertain at the moment in the treatment of antibiotic-resistant Gram-negative bacteria. All of the possible “new” agents have drawbacks. Although in my opinion Ceftazidime-avibactam, Aztreonam-avibactam and Cefiderocol show some promise and may well become antibiotics I use more frequently in the future.
The scenarios I can see me using these are:
- Ceftazidime-avibactam – confirmed or highly suspected infection with non-NDM enterobacteriaceae, or empirically in combination with Teicoplanin and Amikacin when multiple antibiotic-resistant bacteria are a possibility
- Aztreonam-avibactam – suspected CPE producing enterobacteriaceae where the mechanism of resistance is unknown, or empirically in combination with Teicoplanin and Amikacin when multiple antibiotic-resistant bacteria are a possibility
- Cefiderocol – suspected antibiotic-resistant Gram-negative infection or known multiple antibiotic-resistant Pseudomonas spp. or Acinetobacter spp., or empirically in combination with Teicoplanin and Metronidazole when multiple antibiotic-resistant bacteria are a possibility
Unfortunately the only one of these currently available on a routine basis is Ceftazidime-avibactam so my choices are still quite limited at present, but the others are on the horizon. Maybe it’s time to buy some shares… just be careful of the conflict of interest!
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