Resistance is Futile, For Now – Overcoming Resistance with Ceftazidime-Avibactam

I think we can all agree that resistance is inevitable, despite what the quote says, in the world of infectious diseases. More and more, the use of broad spectrum antibiotics (looking at you, vanco-zosyn!) brings upon more resistant organisms, with beta-lactamases being one of the key methods of resistance in many gram negative bacteria. As you may or may not know, things like clavulonic acid, tazobactam, and sulbactam do not “broaden” coverage, but merely inhibit the certain beta-lactamases to “restore” the susceptibility of the parent antibiotic. Given the rise in other types of beta-lactamases, especially NDM and KPC, these guys may not work much for infections with certain strains of organisms. As a result, in the past few years there has been the release of a new type of beta-lactamase inhibitors into the market: avibactam and vaborbactam. 

Here, we will focus on avibactam, which is in the combination ceftazadime-avibactam aka Avycaz (which I will call CAZ-AVI from now on). Ceftazadime is the parent antibiotic, a third-generation cephalosporin with a niche in pseudomonas infections, which makes it a bit different from others in the class (i.e. ceftriaxone) in that respect. The “ESKAPE” organisms (different from ampC producing “ESCAPE” aka E. faecium, S. aureus, K. pneumo, A. baumanii, P. aureginosa, and Enterobacter species) are unique pathogens in that they tend to “escape” the most commonly used antibiotics (1). Many of the gram negatives mentioned tend to produce “beta-lactamases” which hydrolyze the beta-lactam ring of the antibiotic, rendering said antibiotic useless in their presence (1). Several beta-lactamase inhibitors bind to these beta-lactamases, allowing the parent antibiotic to produce its killing effect and bind to bacterial penicillin-binding proteins. Tazobactam, which inhibits class A and some class C beta-lactamases, binds irriversibely to these to exert their effect. One of the unfortunate things about the older beta-lactamase inhibitors is their narrow spectrum of activity in terms of beta-lactamases (2); in general, they do not do much for Class A carbapenamases or Class C. Avibactam, a novel, nonbeta-lactam beta-lactamase has activity against most Ambler Class A enzymes (the carbapenamase component at least), as well as Class C (the “ampC” producers) and some Class D which include carbapenamases. Compared with the more “classical” beta-lactamase inhibitors, avibactam is a non-beta-lactam beta-lactamase inhibitor which has activity against class A, C, and some class D enzymes, allowing a broader spectrum of activity (3). Further, the inhibition process is reversible for avibactam as compared to tazobactam. While this combination, CAZ-AVI restores activity to ESBLs and inhibits several carbapenamases (see later), it has no activity against acinetobacter spp or stenotrophomonas maltophilia as they have different mechanisms of resistance. While this may sound like a bunch of gibberish, it essentially means that you can use CAZ-AVI for ESBL, ampC producers, and some carbapenam-resistant organisms (not all, there are notable exceptions).

SUSCEPTIBILITY DATA

Data from the INFORM global surveillance study found that ceftazidime-avibactam inhibited nearly all isolates with ESBLs, amp-C beta-lactamases, or both (4):

In another study, susceptibility rates for ceftazidime-avibactam and comparator agents suggested that CAZ-AVI had higher percentage of susceptible isolates for pseudomonas and enterobacteriaceae when compared to meropenem, though lower when compared to colistin (5):

Not surprisingly, CAZ-AVI is not able to inhibit beta-lactamases associated with acinetobacter so it had little activity. 

CLINICAL DATA

The above seems all well and good, but we have discussed in the past that breakpoints do not necessarily mean that it will be clinically effective, as this number is a combination of factors that have to take into account the rate of clinical success as well as adverse events. Several major trials have compared CAZ-AVi in a variety of clinical settings. The REPRISE study (6), which was a phase III, randomized trial evaluating CAZ-AVI with best available therapy in complicated UTI or intra-abdominal infections with MDROs. 333 patients were randomized, with most of the comparator group being given meropenem or imipenem. In both cohorts, cure rates were similar (90.9%, 95% CI 86-95 for CAZ-AVI; 91.2%, 95% CI 86-95 for best available therapy):

While the graph above suggests that CAZ-AVI had better outcomes in cIAI, given the low numbers it is difficult to draw any meaningful conclusions. Similarly, the RECAPTURE trial compared CAZ-AVI and Doripenem in patients with acute complicated UTI or pyelonephritis in a randomized, phase III, double-blind trial involving 1033 patients (7). There was no difference between groups in patient assessed symptomatic resolution at day 5 (70% for CAZ-AVI vs 66% for Doripenem, difference 4%, 95% CI 2.39 to 10.42) though favorable microbiological response and test of cure, which occurred at 21-25 days after randomization, favored CAZ-AVI (77% vs 71%, difference 6.44, 95% CI 0.33-12.36). When compared to imipenem-cilastatin, an RCT of 137 patients (8) found that both CAZ-AVI imipenem-cilastatin had comparable microbiological response at the test of cure visit (70.4% in CAZ-AVI and 71.4% in imipenem-cilastatin, difference -1.1%, 95% CI -27 to 25), though very few patients were found to have MDRO (roughly 20).

Randomized data for intra-abdominal infections is sparse when compared to urinary tract infections. A double-blind, multicenter, randomized trial evaluated CAZ-AVI/Metronidazole and meropenem/placebo in a 1:1 fashion for complicated intra-abdominal infections (9). Primary endpoint was clinical cure at test-of-cure visit 28-35 days after randomization. 1066 patients were randomized, with non-inferiority primary endpoint being achieved in the modified ITT analysis:

Notably, patients who had moderate renal impairment tended to do better with meropenem. Similar to some of the above studies, only 13% of patients had isolates that were resistant to ceftazidime at baseline, and just above 60 were infected with pseudomonas, making it difficult to drawn conclusions on how they perform on more resistant pathogens:

Only one trial has been performed for pneumonia, though I think this is more applicable to the situations where CAZ-AVI will actually be used in. The REPROVE trial, which randomized 879 patients to either ceftazidime-avibactam or meropenem for nosocomial pneumonia found that in the modified ITT and the clinical evaluable population the clinical cure rates at TOC were comparable between groups (10):

All cause mortality was also similar (9.4% in the CAZ-AVI group vs 7.4% in the meropenem group) and there was no difference in outcomes when stratifying patients by organism. 

In a dedicated FDA analysis of the phase III REPROVE study (11) CAZ-AVI was noninferior to meropenem in the ITT population for 28-day all cause mortality (9.6% vs 8.3%). Similarly, in ceftaz-non susceptible isolates, there was no difference in mortality between groups (CAZ-AVI, 8.2% [4/49]; meropenem, 8.5% [5/59]).

One of the things you may have noticed is there is little in the way of data as to how this antibiotic is typically used in the clinical setting i.e MDR organisms. This has to do (I think) with the fact it is easier to recruit for more “common” issues such as UTIs than for MDRO infections specifically, and the manufacturer would like to get approval and not risk having a dedicated cohort of super sick patients, who may bias the results one way. Further, I think it may be due to the relative rarity of such infections as well. Despite this, some insights can be gained from teh above studies. When looking at pooling patients with MDR Enterobacteriaceae and Pseudomonas isolates from the above trials (12), favorable responses were seen in both the CAZ-AVI group and the comparator group (78.4% vs 71.6% for Enterobacteriacae and 57.1% vs 53.8% for Pseudomonas). 

CARBAPENAMASE RESISTANCE

I think this is where most of the use of CAZ-AVI is going to go into. It should be noted that not all carbapenamases are created equal. In general, CAZ-AVI tends to have activity against KPC-producing Enterobacteriacae, as well as against OXA-48 beta-lactamases (13). A Brazilian study of 307 carbapenem-nonsusceptible P. aeruginosa isolates found that 73% of these were susceptible to ceftaz-avibactam, however it had no susceptibility to metallo-beta lactamases, such as NDM or VIM (14) which tend to be class B:

Indeed, an observational, retrospective study evaluated infections with OXA-48 carbapenamase-producing enterobacteriacae (15). 57 patients were evaluated, of which 46 received monotherapy with CAZ-AVI. All had previously received therapy with colistin plus imipenem, and clinical/microbiological cure were achieved in 77% and 65%, respectively, with all-cause mortality at 14 and 30 days being 14% and 22%, respectively. 

From here on, however, data is not as robust and limited to relatively small observational cohorts that used propensity score matching and multivariate regression analysis to draw some conclusions. A small case series (16) of 13 patients with CRE who were treated with CAZ-AVI were compared with 28 control patients, and found that rates of clinical remission, clinical cure at 30 days, and all-cause mortality at 30 days were not statistically different:

In another observational study where CAZ-AVI was used for carbapenem-resistant infections as salvage therapy, 104 cases were compared with 104 controls (17). Cases tended to be younger, but also more likely to have SOT and have higher co-morbidity indices:

 day mortality was lower in the cases (36.5%) compared to controls (55.8%, p = 0.005) with multivariate analysis finding that any regimen that contained CAZ-AVI was associated with lower 30-day mortality:

A multicenter, retrospective, observational cohort involving 203 patients with CRE or MDR Pseudomonal infections found that initiation of CZA within 48 hours was associated with lower mortality in multivariate logistic regression analysis (18):

How well does CAZ-AVI perform against, lets say, colistin? A prospective, observational study, CAZ-AVI was compared to colistin in carbapenem-resistant enterobacteriaceae (19). 99 received colisitin while 38 received avycaz, of which 97% were infected with K. pneumo. All cause mortality was lower in the CAZ-AVI group (8% vs 33%), which remained significant after IPTW adjustment (9% vs 32%, p=0.001). Probability of better outcome was better for CAZ-AVI (64% probability)

Another retrospective, multicenter study evaluated CAZ-AVI and colistin in patients with CRE bacteremia (20). Primary outcome was 14-day mortality. 61 patients (32 in Avycaz and 29 in colistin) were evaluated. 14 day mortality was lower in the CAZ-AVI group (19% vs 31%), though this was not statistically significant. Ceftaz-avibactam was associated with a lower 14-day adjusted mortality, but this pattern did not hold true for 30 day adjusted mortality.

Patients in the CAZ-AVI group were more likely to have prolonged bacteremia prior to therapy, less likely to have carbapenem combination therapy, and more likely to have received a solid organ transplant.

A retrospective study (21) evaluated both tigecycline and CAZ-AVI for CR K. pneumo HAP/VAP and found that cure rate was higher in the CAZ-AVI group (51% vs 29%, p=0.022), as was microbiological cure rate (74.4% vs 33.9%, p < 0.001). 28 day survival was not statistically different, however (69.8% for CAZ-AVI vs 66.1% for tigecycline). Despite this, multivariate analysis found that CAZ-AVI was associated with higher clinical cure rates and microbiological success, though there was no association with 28-day survival:

TL;DR

• Beta-lactamases are a major resistance mechanism in various bacteria; they cleave off the beta-lactam ring
• Different beta-lactamases are inhibited by different beta-lactamase inhibitors
• Avibactam, a non-beta lactam beta-lactamase inhibitor, works on a majority of substrates, with the major exception being Ambler class B (works on ampC, ESBLs, OXA carbapenamases, KPC, but NOT metallo-beta-lactamse such as NDM
• Does not work on Acinetobacter or stenotrophomonas. Sorry
• Approved for UTIs and complicated intra-abdominal infections. 
• Some decent retrospective data when compared to carbapenems, and may be a reasonable option when compared to colistin and tigecycline for infections with MDROs. 

References:

1. Zhanel GG, Chung P, Adam H, Zelenitsky S, Denisuik A, Schweizer F, Lagacé-Wiens PR, Rubinstein E, Gin AS, Walkty A, Hoban DJ, Lynch JP 3rd, Karlowsky JA. Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 2014 Jan;74(1):31-51. doi: 10.1007/s40265-013-0168-2. PMID: 24352909.
2. Hidalgo JA, Vinluan CM, Antony N. Ceftazidime/avibactam: a novel cephalosporin/nonbeta-lactam beta-lactamase inhibitor for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. Drug Des Devel Ther. 2016 Jul 26;10:2379-86. doi: 10.2147/DDDT.S110946. PMID: 27528799; PMCID: PMC4970634.
3. Shirley M. Ceftazidime-Avibactam: A Review in the Treatment of Serious Gram-Negative Bacterial Infections. Drugs. 2018 Apr;78(6):675-692. doi: 10.1007/s40265-018-0902-x. PMID: 29671219.
4. Karlowsky JA, Biedenbach DJ, Kazmierczak KM, Stone GG, Sahm DF. Activity of Ceftazidime-Avibactam against Extended-Spectrum- and AmpC β-Lactamase-Producing Enterobacteriaceae Collected in the INFORM Global Surveillance Study from 2012 to 2014. Antimicrob Agents Chemother. 2016 Apr 22;60(5):2849-57. doi: 10.1128/AAC.02286-15. PMID: 26926635; PMCID: PMC4862475.
5. Sader HS, Castanheira M, Flamm RK. Antimicrobial Activity of Ceftazidime-Avibactam against Gram-Negative Bacteria Isolated from Patients Hospitalized with Pneumonia in U.S. Medical Centers, 2011 to 2015. Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02083-16. doi: 10.1128/AAC.02083-16. PMID: 28069649; PMCID: PMC5365649.
6. Carmeli, Y., Armstrong, J., Laud, P.J. orcid.org/0000-0002-3766-7090 et al. (4 more authors) (2016) Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. The Lancet Infectious Diseases, 16 (6). Pp. 661-673. ISSN 1473-3099 https://doi.org/10.1016/S1473-3099(16)30004-4
7. Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, Yates K, Gasink LB. Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program. Clin Infect Dis. 2016 Sep 15;63(6):754-762. doi: 10.1093/cid/ciw378. Epub 2016 Jun 16. PMID: 27313268; PMCID: PMC4996135.
8. Vazquez JA, González Patzán LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka J, Sable C. 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 Dec;28(12):1921-31. doi: 10.1185/03007995.2012.748653. Epub 2012 Nov 21. PMID: 23145859.
9. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, Llorens L, Newell P, Pachl J. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis. 2016 Jun 1;62(11):1380-1389. doi: 10.1093/cid/ciw133. Epub 2016 Mar 8. PMID: 26962078; PMCID: PMC4872289.
10. Torres, A., Zhong, N., Pachl, J. et al. (8 more authors) (2018) Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infectious Diseases, 18 (3). pp. 285-295. ISSN 1473-3099
11. Torres A, Rank D, Melnick D, Rekeda L, Chen X, Riccobene T, Critchley IA, Lakkis HD, Taylor D, Talley AK. Randomized Trial of Ceftazidime-Avibactam vs Meropenem for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (REPROVE): Analyses per US FDA-Specified End Points. Open Forum Infect Dis. 2019 Apr 25;6(4):ofz149. doi: 10.1093/ofid/ofz149. PMID: 31041348; PMCID: PMC6483139.
12. Stone GG, Newell P, Gasink LB, Broadhurst H, Wardman A, Yates K, Chen Z, Song J, Chow JW. Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: pooled data from the ceftazidime/avibactam Phase III clinical trial programme. J Antimicrob Chemother. 2018 Sep 1;73(9):2519-2523. doi: 10.1093/jac/dky204. PMID: 29912399.
13. Pogue JM, Bonomo RA, Kaye KS. Ceftazidime/Avibactam, Meropenem/Vaborbactam, or Both? Clinical and Formulary Considerations. Clin Infect Dis. 2019 Jan 18;68(3):519-524. doi: 10.1093/cid/ciy576. PMID: 30020449.
14. Carmen Antonia Sanches Ito, Larissa Bail, Lavinia Nery Villa Stangler Arend, Keite da Silva Nogueira & Felipe Francisco Tuon (2021) The activity of ceftazidime/avibactam against carbapenem-resistant Pseudomonas.aeruginosa, Infectious Diseases, 53:5, 386-389, DOI: 10.1080/23744235.2020.1867763
15. Sousa A, Pérez-Rodríguez MT, Soto A, Rodríguez L, Pérez-Landeiro A, Martínez-Lamas L, Nodar A, Crespo M. Effectiveness of ceftazidime/avibactam as salvage therapy for treatment of infections due to OXA-48 carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother. 2018 Nov 1;73(11):3170-3175. doi: 10.1093/jac/dky295. PMID: 30099490.
16. Alraddadi, B.M., Saeedi, M., Qutub, M. et al. Efficacy of ceftazidime-avibactam in the treatment of infections due to Carbapenem-resistant Enterobacteriaceae. BMC Infect Dis 19, 772 (2019). https://doi.org/10.1186/s12879-019-4409-1
17. Tumbarello M, Trecarichi EM, Corona A, De Rosa FG, Bassetti M, Mussini C, Menichetti F, Viscoli C, Campoli C, Venditti M, De Gasperi A, Mularoni A, Tascini C, Parruti G, Pallotto C, Sica S, Concia E, Cultrera R, De Pascale G, Capone A, Antinori S, Corcione S, Righi E, Losito AR, Digaetano M, Amadori F, Giacobbe DR, Ceccarelli G, Mazza E, Raffaelli F, Spanu T, Cauda R, Viale P. Efficacy of Ceftazidime-Avibactam Salvage Therapy in Patients With Infections Caused by Klebsiella pneumoniae Carbapenemase-producing K. pneumoniae. Clin Infect Dis. 2019 Jan 18;68(3):355-364. doi: 10.1093/cid/ciy492. PMID: 29893802.
18. Jorgensen SCJ, Trinh TD, Zasowski EJ, Lagnf AM, Bhatia S, Melvin SM, Steed ME, Simon SP, Estrada SJ, Morrisette T, Claeys KC, Rosenberg JR, Davis SL, Rybak MJ. Real-World Experience With Ceftazidime-Avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections. Open Forum Infect Dis. 2019 Dec 6;6(12):ofz522. doi: 10.1093/ofid/ofz522. PMID: 31890725; PMCID: PMC6934163.
19. van Duin D, Lok JJ, Earley M, Cober E, Richter SS, Perez F, Salata RA, Kalayjian RC, Watkins RR, Doi Y, Kaye KS, Fowler VG Jr, Paterson DL, Bonomo RA, Evans S; Antibacterial Resistance Leadership Group. Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae. Clin Infect Dis. 2018 Jan 6;66(2):163-171. doi: 10.1093/cid/cix783. PMID: 29020404; PMCID: PMC5850032.
20. Hakeam HA, Alsahli H, Albabtain L, Alassaf S, Al Duhailib Z, Althawadi S. Effectiveness of ceftazidime-avibactam versus colistin in treating carbapenem-resistant Enterobacteriaceae bacteremia. Int J Infect Dis. 2021 Aug;109:1-7. doi: 10.1016/j.ijid.2021.05.079. Epub 2021 Jun 4. PMID: 34091006.
21. Shirley M. Ceftazidime-Avibactam: A Review in the Treatment of Serious Gram-Negative Bacterial Infections. Drugs. 2018 Apr;78(6):675-692. doi: 10.1007/s40265-018-0902-x. PMID: 29671219.
22.