In this article an infectious diseases pharmacist provides perspective on four key questions about ceftazidime-avibactam (Avycaz), a new antibiotic used for treating infections caused by multi-drug resistant Gram negative bacteria.
Authored By: Madeline King, Pharm.D.
[Last updated: 9 November 2017]
If you live anywhere that sees a lot of multi-drug resistant (MDR) Gram negatives, you may often find yourself pondering over a susceptibility report that offers you few treatment options. Different infectious diseases practitioners and pharmacists may choose different regimens to treat MDR organisms, and based on available literature, there is frequently no one “right” answer.
We often use two or more drugs to eradicate MDR Gram negative organisms, potentially at the expense of the patient’s kidneys (e.g., colistin, aminoglycosides). Combinations often include a carbapenem plus an aminoglycoside or a polymyxin, and may also include tigecycline, or fosfomycin (usually outside the US) [1]. Dual carbapenem therapy has also been utilized too [2].
Infections due to carbapenem-resistant Enterobacteriaceae (CRE) result in high morbidity and mortality, as well as increased healthcare costs. Mortality rates of up to 60% were seen in several studies of patients with CRE infections, and higher mortality was typically seen in patients receiving monotherapy [3,4].
Ceftazidime-avibactam (Avycaz) is a new cephalosporin/ beta-lactamase inhibitor combination active against carbapenem-resistant Enterobacteriaceae infections, but only FDA approved in the United States for urinary tract infections (UTIs) and intra-abdominal infections [5].
Avibactam is active against Ambler class A, C, and D β-lactamses, which includes carbapenemases but not metallo-beta-lactamases [6]. It is unique in that it is a reversible beta-lactamase inhibitor, meaning it binds beta-lactamase enzymes, but the bond is deacylated and the drug can be recycled [7]. In combination with an older, well-studied cephalosporin (ceftazidime), it demonstrated efficacy in patients with complicated UTIs and intra-abdominal infections, and was approved based on phase II studies for those indications [8,9].
Retrospective evaluations of ceftazidime-avibactam use have shown some positive outcomes in other infections and make us hopeful that it is an effective option for our more severely ill patients, such as those with bacteremia and pneumonia caused by CRE.
As we learn more about ceftazidime-avibactam it may be helpful to make concise summaries available to practitioners. With this in mind, here I provide perspective on four key questions about ceftazidime-avibactam…
1. When can ceftazidime-avibactam be considered?
In vitro, ceftazidime-avibactam has shown activity against a variety of isolates, including ceftazidime-resistant and carbapenem-resistant gram-negative organisms (namely Enterobacteriaceae and Pseudomonas aeruginosa). It does not restore activity of ceftazidime against Acinetobacter or Burkholderia, because of their specific resistance mechanisms to ceftazidime [10].
At this time, there are no studies specifically comparing ceftazidime-avibactam as monotherapy to another regimen for CRE infections. A case series reported on three patients with bacteremia who received ceftazidime-avibactam as salvage therapy all survived to hospital discharge, without subsequent readmission [11]. Larger retrospective case series of up to 60 patients have demonstrated up to 76% survival for patients receiving ceftazidime-avibactam either as monotherapy or as part of a combination for CRE infections from various sources, including bacteremia. These studies included critically ill, as well immunosuppressed patients [12-14].
Fewer studies have evaluated ceftazidime-avibactam for Pseudomonas infections. A small multi-center case series of 10 patients showed 80% survival and only one patient with microbiologic failure, however half of the patients received concomitant therapy [15]. A case report of 2 patients with extensively drug-resistant Pseudomonas aeruginosa reported good outcomes in both patients after switching from meropenem plus colistin to ceftazidime-avibactam plus colistin [16].
Ceftazidime-avibactam, therefore, can be considered for patients with MDR Enterobacteriaceae or MDR Pseudomonas infections.
2. When should ceftazidime-avibactam be avoided?
Based on a recent study where susceptibility to ceftazidime-avibactam was tested before and during therapy, there is a potential to develop resistance on therapy, and therefore it is not ideal to use ceftazidime-avibactam alone if susceptibility testing cannot be performed.
Shields and colleagues in Pittsburgh found that isolates of K. pneumoniae developed resistance to ceftazidime-avibactam while on therapy after 10-19 days of receiving the drug. They found mutations in blaKPC-3. Interestingly, this restored carbapenem susceptibility in some isolates [17].
Ceftazidime-avibactam may not be useful alone if susceptibility testing cannot be performed, especially in critically ill patients. Providers should also take into account allergy histories prior to using ceftazidime-avibactam.
3. What are ceftazidime-avibactam dosing concerns for patients with renal dysfunction?
Initially, Phase II studies showed worse outcomes in patients who had renal dysfunction, but patients may have also been under-dosed.
Shields and colleagues saw worse outcomes in patients receiving continuous renal replacement therapy (CRRT), however a multi-center study did not see the same results. There are currently no dosing recommendations from the manufacturer for patients receiving CRRT.
In my institution, we have used ceftazidime dosing to guide ceftazidime-avibactam dosing for patients receiving CRRT. Based on the low potential for toxicity and concern for poor outcomes when lower doses are used, I prefer to use these established ceftazidime doses despite not having information to guide avibactam dosing for patients on CRRT.
4. What other antibiotics should be considered for use with ceftazidime-avibactam?
For less severe infections caused by CRE, such as UTIs, ceftazidime-avibactam may be used monotherapy, especially if susceptibility testing is available. For more severe infections or in patients who are critically ill, it is probably advisable to consider a combination of ceftazidime-avibactam plus another susceptible agent, such as an aminoglycoside.
Although not specifically studied, it is reasonable to consider adding an inhaled antibiotic (e.g., tobramycin, colistin) for pneumonia caused by CRE. The retrospective studies to date have included patients receiving a variety of concomitant antibiotics and have not shown differences in outcomes between patients receiving monotherapy or combination therapy.
Closing comments
In general, more studies evaluating patients receiving ceftazidime-avibactam for a range of infections varying in severity should be completed. More data is also needed for patients receiving renal replacement therapy.
Ceftazidime-avibactam is a reasonable option to consider for CRE infections, but susceptibility testing should be done before use, and during use if the patient is unable to demonstrate microbiological clearance of the organism, since the development of resistance on therapy has been shown.
In critically ill patients, combination therapy may be beneficial, despite a lack of evidence for specific combination regimens.
Disclosures
The author reports no conflicts of interest.
REFERENCES
1. Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. Open Forum Infect Dis. 2015;2(2):ofv050.
2. Cprek JB, Gallagher JC. Ertapenem-Containing Double-Carbapenem Therapy for Treatment of Infections Caused by Carbapenem-Resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2015;60(1):669-73.
3. Borer A, Saidel-Odes L, Riesenberg K, Eskira S, Peled N, Nativ R, et al. Attributable mortality rate for carbapenem-resistant Klebsiella pneumoniae bacteremia. Infect Control Hosp Epidemiol. 2009;30(10):972-6.
4. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012;55(7):943-50.
5. Actavis. Avycaz (Ceftazidime-avibactam). Prescribing Information. Cincinnati, OH: Forest Pharmaceuticals, Inc; 2016.
6. Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, Lagace-Wiens PR, et al. Ceftazidime-avibactam: a novel cephalosporin/beta-lactamase inhibitor combination. Drugs. 2013;73(2):159-77.
7. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, et al. Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A. 2012;109(29):11663-8.
8. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68(5):1183-92.
9. Vazquez JA, Gonzalez Patzan LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka J, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012;28(12):1921-31.
10. Lagace-Wiens P, Walkty A, Karlowsky JA. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014;9:13-25.
11. Wu G, Abraham T, Lee S. Ceftazidime-Avibactam for Treatment of Carbapenem-Resistant Enterobacteriaceae Bacteremia. Clin Infect Dis. 2016;63(8):1147-8.
12. King M, Heil E, Kuriakose S, Bias T, Huang V, El-Beyrouty C, et al. Multicenter Study of Outcomes with Ceftazidime-Avibactam in Patients with Carbapenem-Resistant Enterobacteriaceae Infections. Antimicrob Agents Chemother. 2017;61(7).
13. Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, et al. Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections. Clin Infect Dis. 2016;63(12):1615-8.
14. Temkin E, Torre-Cisneros J, Beovic B, Benito N, Giannella M, Gilarranz R, et al. Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Carbapenem-Resistant Organisms. Antimicrob Agents Chemother. 2017;61(2).
15. King M, Huang V, Heil E, Gallagher JC. Outcomes with ceftazidime/avibactam in patients with Pseudomonas infections: a multi-center study. Poster presented at: ID Week2016.
16. Xipell M, Bodro M, Marco F, Losno RA, Cardozo C, Soriano A. Clinical experience with ceftazidime/avibactam in patients with severe infections, including meningitis and lung abscesses, caused by extensively drug-resistant Pseudomonas aeruginosa. Int J Antimicrob Agents. 2017;49(2):266-8.
17. Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, et al. Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections. Antimicrob Agents Chemother. 2017;61(3).
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