Ceftazidime-avibactam (Avycaz), meropenem-vaborbactam (Vabomere), and ceftolozane-tazobactam (Zerbaxa) are three new beta-lactam/beta-lactamase inhibitor combination antibiotics that have gained FDA approval in recent years. In this article a comparison of Avycaz, Vabomere, and Zerbaxa is provided.
Authored By: Timothy P. Gauthier, Pharm.D., BCPS-AQ ID & Krutika N. Mediwala, Pharm.D., BCPS
Originally published: 16 October 2017
Last updates made: 27 November 2019
The crisis of “bad bugs, no drugs” has led to the Infectious Diseases Society of America 10 X ’20 initiative, the National Action Plan for Combating Antibiotic-Resistant Bacteria, CARB-X, and other efforts to combat or call attention to drug-resistant bacteria. In examining the issues with resistance in Gram negative bacteria, many problems persist, but there has been some progress. In recent years there have been three new beta-lactam/ beta-lactamase inhibitor combinations to gain FDA approval and come to the market in the United States. These drugs are:
The addition of these agents to the existing antimicrobial arsenal has been a welcomed occurrence as antibiotic-resistant pathogens challenge clinicians and threaten the lives of patients. In particular, we welcome these agents for their activity versus drug-resistant Gram negative pathogens such as carbapenem-resistant Enterobacteriaceae (CRE) and multidrug-resistant Pseudomonas aeruginosa.
As new drugs come to the market it can be a challenge to identify when to use them or when to avoid them. This article seeks to assist with this by providing a comparison of Avycaz, Vabomere, and Zerbaxa.
DISCLAIMER: It should be noted that an exhaustive review comparing these agents is beyond our scope and this article attempts to focus on practical, real-world considerations. In addition readers are cautioned that aspects of this are incredibly complex, this is an attempt at providing general guidance, and there is almost always an exception to every “rule” in infectious diseases.
Ceftazidime-avibactam (Avyaz)
Ceftazidime is a 3rd-generation cephalosporin and avibactam is a reversible non-beta-lactam beta-lactamase inhibitor. Ceftazidime is a veteran antibiotic that has been available individually since FDA-approved in 1985, but avibactam is a rookie on the market currently only available in this combination product. Avibactam is active against ESBLs, KPC enzymes, and OXA-48 carbapenemases. It is not active against metallo-beta-lactmases.
The addition of avibactam to ceftazidime expands coverage to a variety of multidrug-resistant Gram negative bacteria, but does close to nothing for expanding Gram positive activity or anaerobic activity.
Ceftolozane-tazobactam (Zerbaxa)
Ceftolozane is a “5th-generation” or “new generation” cephalosporin that is structurally similar to ceftazidime (with a different side chain) and tazobactam is a beta-lactamase inhibitor. Prior to Zerbaxa coming to the market, tazobactam was only available as a component of piperacillin-tazobactam (Zosyn) and ceftolozane was not available. While the tazobactam component offers the benefit of inhibiting some beta-lacatamases, ceftolozane may also be less impacted by the over-expression of efflux pumps, as compared to other beta-lactams (e.g., imipenem-cilastatin). Tazobactam can prevent many ESBLs and cephalosporinases from impacting ceftolozane, but less so for AmpC beta-lactamases or carbapenemases.
Ceftolazone-tazobactam demonstrates excellent activity against a number of multidrug resistant Gram negative bacteria, including ceftazidime and carbapenem-resistant strains of Pseudomonas aeruginosa. Ceftolozane-tazobactam does not have good activity versus ceftazidime-resistant Enterobacter species or carbapenem-resistant Enterobacteriaceae.
Meropenem-vaborbactam (Vabomere)
Meropenem is a carbapenem antibiotic and vaborbactam is a beta-lactamase inhibitor. Meropenem was FDA-approved in the United States in July of 1996 and is used today for a variety of infections including pneumonia, bacteremia, osteomyelitis, urinary tract infection, and meningitis. Vaborbactam is a novel, non-suicidal beta-lactamase inhibitor without any antimicrobial activity that is only currently available in this combination product.
Like avibactam and tazobactam, vaborbactam protects its beta-lactam from degradation by enzymes produced by multidrug-resistant Gram negative bacteria. Of note, vaborbactam does not improve the effect of meropenem versus Acinetobacter spp. or Pseudomonas spp. Vaborbactam also does not work against metallo-beta-lactamases.
Common ground and differences
This table provides a comparison of Avycaz, Vabomere, and Zerbaxa. The factors selected for inclusion were picked due to their likely clinical relevance. Note that all of these agents are available as intravenous only. Note also that some items are somewhat subjective (e.g., ability to cover Pseudomonas) and in these circumstances the information represents the opinions of the authors.
|
Table 1. Comparison of Avycaz, Vabomere, and Zerbaxa |
|||
|
Ceftazidime-avibactam (Avycaz) |
Ceftolozane-tazobactam
(Zerbaxa) |
Meropenem-vaborbactam (Vabomere) |
|
| FDA-approval |
February 2015 |
January 2016 |
August 2017 |
| Manufacturer |
Allergan |
Merck |
The Medicines Company |
| Novel compound |
Avibactam |
Ceftolozane |
Vaborbactam |
| PK/PD |
Time>MIC |
Time>MIC |
Meropenem: Time>MIC Vaborbactam: AUC/MIC |
| FDA-indicated for cIAI |
Yes (with metronidazole) |
Yes (with metronidazole) |
No |
| FDA-indicated for cUTI |
Yes |
Yes |
Yes |
| Pseudomonas activity |
Yes |
Yes |
Yes |
| Carbapenemase-producing Enterobacteriaceae activity |
Yes |
No* |
Yes |
| MRSA activity |
No |
No |
No |
| Usual dose |
2.5 grams |
1.5 grams or 3 grams |
4 grams |
| Usual frequency |
8 hours |
8 hours |
8 hours |
| Infusion duration |
2 hours |
1 hour |
3 hours |
| Renal dose adjustment |
CrCl < 50 mL/min |
CrCl < 50 mL/min |
eGFR < 50 mL/min |
| Hepatic dose adjustment |
No |
No |
No |
| Best stability room temperature |
12 hours |
24 hours |
4 hours |
| Best stability refrigerated |
24 hours +12 hours room temperature |
7 days |
22 hours |
| Vial size |
2.5 grams |
1.5 grams |
2 grams |
| Approximate AWP per vial (cost per day)** |
$359 ($1,077) |
$103 ($310) |
$165 ($990) |
Abbreviations: ABSSSI = acute bacterial skin and skin structure infection, AUC = area under the curve, AWP = average wholesale price, CrCl = creatinine clearance, cIAI = complicated intra-abdominal infection, eGFR = estimated glomerular filtration rate, MIC = minimum inhibitory concentration, MRSA = methicillin-resistant Staphylococcus aureus, PK = pharmacokinetic, PD = pharmacodynamic, UTI = urinary tract infection
*Amended 6 September 2018 to improve clarity: this row was changed from “carbapenem resistant Enterobacteriaceae” to “carbapenemase-producing Enterobacteriaceae.” In addition ceftolozane-tazobactam was changed from “yes” to “no.” Ceftolozane-tazobactam can have activity versus carbapenem-resistant Enterobacteriaceae, however it does not provide coverage for carbapenemase producers.
**Prices may change and may vary depending on institutional contracting. Cost per day provided for patient with normal kidney function. These costs were as of 2017.
Gram negative resistance & the Ambler classes
Since these drugs are mainly going to be used for drug-resistant Gram negative bacteria, it is worth discussing some of their differences in this capacity. For Gram positive and anaerobic coverage, readers are referred to the package inserts and scientific literature, as that is expected to be a less relevant clinical topic.
There are several different mechanisms of bacterial resistance, but one of the most common ones is through enzymes that degrade antibiotics. Beta-lactamases are types of enzymes that fall into this category. There are many different types of beta-lactamases that bacteria can produce. The Ambler classification is one way to categorize them.
The Ambler classification divides beta-lactamases into for classes: A, B, C, and D. This table provides a summary of the Ambler classes. Note that bacteria can produce multiple types of beta-lactamases at one time and can also have other resistance mechanisms simultaneously (e.g., efflux pumps, porin channels, etc.), so this is only one piece of a larger puzzle.
| Ambler Class Summary | ||||
|
Ambler Class |
Beta-lactamase Type |
Activity | Enzyme Examples |
Common Bacteria |
|
A |
Penicillinases |
Hydrolizes penicillins and cephalosporins | CTX-M, KPC, SHV, TEM |
E. coli, Klebsiella, Enterobacteriaceae, Pseudomonas |
|
B |
Metallo-beta-lactamases |
Uses zinc for hydrolysis of beta-lactam ring | IMP, NDM, VIM |
Pseudomonas, Acinetobacter |
|
C |
Cephalosporinases |
Hydrolyzes broad and extended-spectrum cephalosporins | AmpC |
Enterobacter, Citrobacter, Proteus, Serratia, Pseudomonas |
|
D |
Oxacillinases |
Beta-lactamase production and reduced permeability or increased efflux | OXA |
Acinetobacter, E. coli, Pseudomonas |
So when will the newer agents have activity for each Ambler class? That is also a complex topic and it really depends on the specific enzyme involved, but this table attempts to simplify it a little. Remember that resistance to virtually any drug is plausible, so a “yes” does not guarantee the drug will work in all scenarios and there may be exceptions that cannot be expressed in this concise fashion.
|
Generalization of Ambler Class Coverage for Newer Agents |
|||
|
Ambler Class of Beta-lactamases |
Ceftazidime-avibactam
(Avycaz) |
Ceftolozane-tazobactam
(Zerbaxa) |
Meropenem-vaborbactam
(Vabomere) |
|
A |
Yes | Partial |
Yes |
|
B |
No | No |
No* |
|
C |
Yes | Partial |
Yes |
| D | Yes | No |
No* |
KEY: no = no activity, partial = some activity, yes = good activity
*Amended 6 September 2018 to improve clarity: these were both previously labeled “partial”, as we had identified publications [example 1, example 2] stating activity of meropenem-vaborbactam versus Ambler class B and D enzymes to be limited, not absent. Considering this is meant to be a generalization and upon review of publications available at this time, we have elected to make this change to “no.” On the topic, vaborbactam alone does not inhibit class b metallo-betalactamase producing isolates.
What to expect from Avycaz, Zerbaxa, and Vabomere
You should expect to see these drugs brought into the discussion when a patient has a Gram negative organism found to be resistant to agents such as carbapenems, cefepime, piperacillin-tazobactam and/or other broad-spectrum drugs. The potential to avoid drugs with high toxicity rates like the polymyxins and aminoglycosides certainly makes these newer agents appealing in the right clinical setting.
When doing a comparison of Avycaz, Zerbaxa, and Vabomere, it is likely that coverage and cost will be two major questions that people will have to answer locally, working with their microbiology and procurement staff, respectively. Cost and procurement should be fairly easy to work out, but getting tests for susceptibility with newer drugs can be a challenge as microbiology staff tries to keep pace with new approvals from FDA and adhere to regulatory requirements.
We should also expect to learn a lot about these drugs in the coming years and their utility for infections that they are not currently FDA-approved for. It is likely they are going to be useful for a wide range of infections.
In closing, we hope that you have found this comparison useful. If you have suggestions for updates or additional resources/ readings, readers are invited to email IDstewardship@gmail.com.
June 2019 miscellaneous updates: In 2017 we learned that ceftazidime-avibactam resistance can occur on therapy for carbapenem-resistant Klebsiella pneumoniae infections due to plasmid-acquired blaKPC3. In 2018 numerous publications came out identifying ceftazidime-avibactam (for the avibactam component) plus aztreonam to treat metallo-beta-lactamase producing organisms. In June 2019, ceftolozane-tazobactam was FDA-approved for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in adults.
July 2019 miscellaneous updates: In July 2019 imipenem-cilastatin-relebactam (Recarbrio) was FDA-approved for complicated urinary tract infection and complicated intra-abdominal infection. Relebactam is a class A/C beta-lactamase inhibitor. The addition of relebactam to imipenem-cilastatin restores imipenem-cilastatin’s activity versus some imipenem-resistant Pseudomonas aeruginosa. It may also be an option from carbapenem-resistant Enterobacteriaceae. Learn more about Recarbrio here.
November 2019 miscellaneous updates: In November 2019 cefiderocol (Fetroja) was FDA-approved for complicated urinary tract infection in adults. Cefiderocol can have activity versus bacteria producing Ambler class A, B, C, or D beta-lactamases. It is particularly noteworthy for it’s activity versus drug-resistant Acinetobaceter, Pseudomonas, and Stenotrophomonas. In September 2019 this publication explored aztreonam plus meropenem-vaborbactam and aztreonam plus ceftazidime-avibactam. Their data suggest that aztreonam plus meropenem-vaborbactam has similar activity to aztreonam plus ceftazidime-avibactam against Enterobacteriaceae producing NDM and other non-OXA-48-like serine β-lactamases. We expect more publications to arise evaluating this topic.
REFERENCES / SUGGESTED READINGS
WORTH KNOWING ABOUT: CDC’s Antibiotic Resistance Lab Network
The Antibiotic Resistance Lab Network (AR Lab Network) supports nationwide lab capacity to rapidly detect antibiotic resistance in healthcare, food, and the community, and inform local responses to prevent spread and protect people. The AR Lab Network includes labs in 50 states, five cities, and Puerto Rico, including seven regional labs and the National Tuberculosis Molecular Surveillance Center (National TB Center). As a whole, the network tracks changes in resistance and helps identify and respond to outbreaks faster. Clinical sites without the ability to test for the agents discussed above should make requests to CDC through their local or state public health departments. Learn more here.
Acknowledgement: We would like to thank Dr. David Nicolau for his input, which led to the changes dated 6 September 2018. We would also like to thank Dr. Richard Brooks for bringing the AR Lab Network to our attention and providing the above information on that topic.
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