Clinical susceptibility breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa for the ceftazidime-avibactam dosage regimen of 2,000/500 mg every 8 h (q8h) by 2-h intravenous infusion (adjusted for renal function) have been established by the FDA, CLSI, and EUCAST as susceptible (MIC, ≤8 mg/liter) and resistant (MIC, >8 mg/liter). The key supportive data from pharmacokinetic/pharmacodynamic analyses, in vitro surveillance, including molecular understanding of relevant resistance mechanisms, and efficacy in regulatory clinical trials are collated and analyzed here.
KEYWORDS: MIC breakpoints, ceftazidime-avibactam
ABSTRACT
Clinical susceptibility breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa for the ceftazidime-avibactam dosage regimen of 2,000/500 mg every 8 h (q8h) by 2-h intravenous infusion (adjusted for renal function) have been established by the FDA, CLSI, and EUCAST as susceptible (MIC, ≤8 mg/liter) and resistant (MIC, >8 mg/liter). The key supportive data from pharmacokinetic/pharmacodynamic analyses, in vitro surveillance, including molecular understanding of relevant resistance mechanisms, and efficacy in regulatory clinical trials are collated and analyzed here.
TEXT
Ceftazidime-avibactam is active in vitro against extended-spectrum β-lactamase-, AmpC-, and serine-carbapenemase (e.g., Klebsiella pneumoniae carbapenemase)-producing Enterobacteriaceae and Pseudomonas aeruginosa but not metallo-β-lactamase (MBL) producers (1–6). Ceftazidime-avibactam clinical breakpoints of susceptible/resistant (MIC, ≤8/>8 mg/liter; tested with a fixed avibactam concentration of 4 mg/liter [7]) have been assigned to Enterobacteriaceae and P. aeruginosa by the U.S. Food and Drug Administration (FDA), Clinical and Laboratory Standards Institute (CLSI), and European Committee on Antimicrobial Susceptibility Testing (EUCAST) for ceftazidime-avibactam 2,000/500 mg every 8 h (q8h) (8–10) based on three key data sources (11–13): probabilities of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) analyses, multinational surveillance, and clinical trials.
PK/PD targets were derived from nonclinical studies for avibactam and from nonclinical and clinical studies for ceftazidime. An established target for ceftazidime, used previously to support ceftazidime breakpoint determinations, is free drug concentrations remaining above the MIC (fT>MIC) for 50% of the dosing interval (13–18). For avibactam to render bacteria functionally negative for β-lactamase (19), it must maintain a critical threshold concentration (CT) for 50% of the dosing interval (20). Conservative CT values for avibactam in combination with ceftazidime considered to correlate with clinical efficacy have been determined as 0.5 mg/liter for up to a 3-log10 CFU reduction in an Enterobacteriaceae hollow-fiber model, 1 mg/liter for bacteriostasis in a P. aeruginosa neutropenic mouse thigh infection model, and 2-log10 killing in a P. aeruginosa neutropenic mouse lung infection model (20–22). PTA analyses for both Enterobacteriaceae and P. aeruginosa used joint PK/PD targets, defined as simultaneous attainment of 50% fT>MIC for ceftazidime and 50% CT>1 mg/liter for avibactam in each patient (20).
Population PK models for ceftazidime and avibactam were developed using PK data from phase 1, 2, and 3 trials (23–25). Because both drugs are excreted predominantly via the kidney, the primary covariate affecting exposure is creatinine clearance (CLCR), necessitating dosage adjustments for patients with CLCR of <50 ml/min (8, 9). Exposure simulations for each compound in 5,000 paired patients per indication (complicated intra-abdominal infections [cIAI], complicated urinary tract infections [cUTI], and nosocomial pneumonia [NP], including ventilator-associated pneumonia [VAP]), and per renal function group incorporated phase 3 patient covariate distributions appropriate to each patient population and between-subject variability; exposure for both ceftazidime and avibactam was simulated in each (virtual) patient to evaluate joint PTA across the whole group (25, 26). Representative PTA curves in cIAI patients (the most conservative indication for PTA) with normal renal function were overlaid with MIC distributions from the International Network for Optimal Resistance Monitoring (INFORM) surveillance program (Fig. 1A and B). The simulations yielded PTA of >94% against bacteria with ceftazidime-avibactam MICs of ≤8 mg/liter; lower PTA values were associated with MICs of 16 or ≥32 mg/liter. Sensitivity analyses for higher PK/PD targets produced PTAs of >90% at joint exposure targets up to 60% fT>MIC (for ceftazidime-avibactam MICs of ≤8 mg/liter) and 60% CT>1 mg/liter (Fig. 1C). Ceftazidime-avibactam dosage adjustments for various degrees of renal impairment also demonstrated high (>98%) PTAs at MICs of ≤8 mg/liter (27). Individual predicted exposures in phase 3 study patients showed no clinically relevant impact on joint target attainment associated with disease severity, obesity, advanced age, or CLCR of >150 ml/min (25, 26). Hence, a susceptible breakpoint of ≤8 mg/liter is consistent with PTA values yielded by the recommended dosage regimens.
FIG 1.
Joint PTA for patients with cIAI and normal renal function receiving ceftazidime-avibactam 2,000/500 mg q8h plotted as a function of ceftazidime-avibactam MIC overlaid with the ceftazidime-avibactam MIC distributions against Enterobacteriaceae (n = 34,062) from the INFORM global surveillance program, 2012 to 2014 (A), overlaid with the ceftazidime-avibactam MIC distributions against Pseudomonas aeruginosa (n = 7,062) from the INFORM global surveillance program, 2012 to 2014 (B), and sensitivity analysis of PTA at different joint PK/PD targets (C). Joint PTA is defined as simultaneous attainment of 50% fT>MIC of ceftazidime-avibactam for ceftazidime and 50% fT>CT of 1 mg/liter for avibactam, with both targets having to be achieved for a simulated patient to be categorized as achieving the joint target. Ceftazidime-avibactam MICs were evaluated with avibactam tested at a fixed concentration of 4 mg/liter. PTA was evaluated for ceftazidime-avibactam MIC values of 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, and 128 mg/liter. The values above the bars are the numbers of isolates tested at each MIC. The arrows show the position of the approved ceftazidime-avibactam-susceptible clinical breakpoint of MIC ≤8 mg/liter (8, 9). This set of isolates of Enterobacteriaceae was also the source of analyses of phenotypically and genotypically defined resistant subpopulations as discussed in the text (3, 4, 6). The isolates of P. aeruginosa were presented and analyzed in detail elsewhere (5).
A key consideration in setting the clinical breakpoint for an antibacterial agent tested against a particular species or group of species is where the putative breakpoint is located on the MIC frequency distribution. The breakpoint should encompass the great majority of the MICs of the drug against contemporary isolates (11) and should not fall on a “peak” in the MIC distribution (13). The clinical breakpoint of ≤8 mg/liter for ceftazidime-avibactam versus P. aeruginosa straightforwardly fit these criteria as follows. Against 7,062 P. aeruginosa isolates collected globally (excluding the United States) in INFORM 2012 to 2014 (Fig. 1B), 92.0% were susceptible to ceftazidime-avibactam (MIC90, 8 mg/liter) (5); more recent analyses, including data from the United States, reported equivalent susceptibility rates (28–34). Of note, 8 mg/liter is at the upper end of the ceftazidime-avibactam MIC distribution, which (as stated above) is an important attribute for the clinical breakpoint (12, 35).
In the case of Enterobacteriaceae, the analysis was not as straightforward, because the breakpoint of ≤8 mg/liter supported by PK/PD target attainment analyses was higher than the MIC90 (0.5 mg/liter) by several doubling dilutions. The global (excluding the United States) INFORM program analyzed 34,062 Enterobacteriaceae isolates collected during 2012 to 2014 (Fig. 1A); 99.5% were inhibited by ≤8 mg/liter ceftazidime-avibactam (MIC90, 0.5 mg/liter) (3), with equivalent susceptibility rates reported from recent analyses that included the United States (29, 31–34, 36). The argument might be made, therefore, that a breakpoint of ≤0.5 or ≤1 mg/liter at the upper end of the mode of MICs would be suitable for the Enterobacteriaceae. However, the following analyses of ceftazidime-avibactam MICs against genotypically and phenotypically characterized antibiotic-resistant subpopulations among Enterobacteriaceae countered that idea. Figure 1A includes meropenem-nonsusceptible isolates (3) and multidrug-resistant (MDR) (resistant to ≥3 classes of antibacterial agents) isolates (6), including 816 MBL-negative meropenem-nonsusceptible isolates. The 90th-percentile ceftazidime-avibactam MIC for these isolates was 4 mg/liter, with 97.7% inhibited by ≤8 mg/liter (3), and the MIC distribution was shifted right compared with the whole distribution, with an upper cutoff of 4 to 8 mg/liter; i.e., the susceptible breakpoint was at the upper end of and did not divide the MIC distribution against this critical phenotypically and genotypically defined subpopulation.
The 34,062 Enterobacteriaceae isolates (Fig. 1A) also included 2,739 MDR Klebsiella pneumoniae and 82 MDR Klebsiella oxytoca isolates. The ceftazidime-avibactam MIC was ≤2 mg/liter against 90% of these isolates and ≤8 mg/liter against 96.6% (6); again, the MIC distribution was shifted right compared with the overall distribution, and the susceptible breakpoint was at the upper end of but did not divide that distribution. From these analyses, it is clear that a breakpoint of ≤8 mg/liter is necessary to encompass important antibiotic-resistant subpopulations, such as carbapenem-resistant or MDR strains.
Phenotypical/genotypical subpopulation analyses of P. aeruginosa were less helpful than analyses of Enterobacteriaceae subpopulations, possibly because the ceftazidime resistance was not mediated by β-lactamase in ∼30% of ceftazidime-nonsusceptible P. aeruginosa, and was therefore not reversed by combination with avibactam (5).
Ceftazidime-avibactam MIC distributions against Enterobacteriaceae and P. aeruginosa isolates from clinical trials in cIAI, cUTI, or NP patients (Fig. 2) were consistent with global INFORM data, apart from a greater proportion of ceftazidime-avibactam-resistant P. aeruginosa, possibly because a relatively high proportion of trial patients were in Eastern Europe, where MBL-producing P. aeruginosa are comparatively common (37, 38). Across the trials, clinical and microbiological response rates were generally comparable, and the results were similar for ceftazidime-avibactam and comparator treatments. Per-pathogen responses were generally similar across indications (39–44); against P. aeruginosa, clinical cure (but not favorable microbiological response) rates were notably lower for patients who received ceftazidime-avibactam versus meropenem in the NP trial (44). Among patients who received ceftazidime-avibactam, favorable microbiological response rates were generally high for infections by Enterobacteriaceae and more variable for those by P. aeruginosa with ceftazidime-avibactam with MICs of ≤8 mg/liter, including ceftazidime-nonsusceptible isolates (Tables 1 and 2). However, consistent with other investigations (45, 46), response rates by MIC did not reveal any trends, possibly because few clinical trial isolates had ceftazidime-avibactam MICs of >8 mg/liter and because MIC-to-outcome correlations may be complicated in cIAI through surgical intervention and in cUTI because of the concentration of some drugs (including ceftazidime and avibactam) in urine.
FIG 2.
Distributions of ceftazidime-avibactam MICs against Enterobacteriaceae (n = 2,615) (A) and Pseudomonas aeruginosa (n = 276) (B) across one phase 2 and five phase 3 prospective clinical trials. The ranges of MICs tested were up to 32 mg/liter in the phase 2 trial and up to 256 mg/liter in the phase 3 trials. The upper limit plotted here was >128 mg/liter, for comparability with Fig. 1. Three Enterobacteriaceae isolates and one P. aeruginosa isolate from the phase 2 trial tested with a ceftazidime-avibactam MIC of >32 mg/liter and are excluded from these frequency distributions. Data pooled from the microbiological modified intent-to-treat populations of the following trials: phase 2 cIAI (NCT00752219 [39]), phase 3 cIAI (RECLAIM 1 and 2 [NCT01499290 and NCT01500239] and RECLAIM 3 [NCT01726023] [40, 43]), phase 3 cUTI (RECAPTURE 1 and 2 [NCT01595438 and NCT01599806] [41]), phase 3 cIAI and cUTI caused by ceftazidime-nonsusceptible pathogens (REPRISE [NCT01644643] [42]), and NP, including VAP (REPROVE [NCT01808092] [44]). Ceftazidime-avibactam MICs were evaluated with avibactam tested at a fixed concentration of 4 mg/liter. The values above the bars are the numbers of isolates tested at each MIC. The arrows show the position of the approved ceftazidime-avibactam-susceptible clinical breakpoint of MIC ≤8 mg/liter (8, 9).
TABLE 1.
Patients with favorable per-pathogen microbiological response at test of cure
| Ceftazidime-avibactam MIC (mg/liter) | No. of patients with favorable response/total with MIC dataa (%) |
||||
|---|---|---|---|---|---|
| Citrobacter freundii | Enterobacter cloacae | Escherichia coli | Klebsiella pneumoniae | Pseudomonas aeruginosa | |
| ≤0.03 | 1/1 (100.0) | 1/1 (100.0) | 66/73 (90.4) | 6/6 (100.0) | — |
| 0.06 | 8/8 (100.0) | 2/2 (100.0) | 234/257 (91.1) | 28/32 (87.5) | — |
| 0.12 | 8/8 (100.0) | 10/12 (83.3) | 163/191 (85.3) | 50/58 (86.2) | — |
| 0.25 | 4/6 (66.7) | 17/19 (89.5) | 53/59 (89.8) | 19/22 (86.4) | — |
| 0.5 | 5/6 (83.3) | 3/5 (60.0) | 16/17 (94.1) | 28/35 (80.0) | 2/2 (100.0) |
| 1 | 1/1 (100.0) | 7/7 (100.0) | 3/4 (75.0) | 27/29 (93.1) | 10/15 (66.7) |
| 2 | — | 1/1 (100.0) | 8/9 (88.9) | 6/6 (100.0) | 34/51 (66.7) |
| 4 | — | 1/3 (33.3) | 1/1 (100.0) | 0/2 (0) | 14/20 (70.0) |
| 8 | — | — | 4/4 (100.0) | — | 10/15 (66.7) |
| 16 | — | — | — | — | 1/3 (33.3) |
| 32 | — | — | — | — | 3/3 (100.0) |
| >32 | — | 0/1 (0) | — | 0/1 (0) | 6/9 (66.7) |
Patients could have >1 pathogen. Microbiological outcomes were categorized as eradication or presumed eradication of the baseline pathogen (i.e., favorable response), persistence or persistence with increasing MIC (i.e., unfavorable response), or indeterminate. Data pooled from the ceftazidime-avibactam arms of the microbiologically evaluable (ME) population of the phase 2 trial in patients with cIAI (NCT00752219 [39]) and the extended ME populations of the phase 3 trials in patients with cIAI (RECLAIM 1 and 2 [NCT01499290 and NCT01500239] and RECLAIM 3 [NCT01726023] [40, 43]), cUTI (RECAPTURE 1 and 2 [NCT01595438 and NCT01599806] [41]), cIAI or cUTI caused by ceftazidime-nonsusceptible pathogens (REPRISE [NCT01644643] [42]), and NP, including VAP (REPROVE [NCT01808092] [44]). Intra-abdominal cultures required an invasive procedure and were obtained only when clinically indicated; therefore, microbiological responses for patients with cIAI were presumed based on clinical outcomes. The empty row indicates the approved ceftazidime-avibactam-susceptible clinical breakpoint of MIC ≤8 mg/liter applied to both Enterobacteriaceae and P. aeruginosa (8, 9).
TABLE 2.
Patients with favorable per-pathogen microbiological response at test of cure for ceftazidime-nonsusceptible pathogens
| Ceftazidime-avibactam MIC (mg/liter) | No. of patients with favorable response/total with MIC dataa (%) |
||||
|---|---|---|---|---|---|
| Citrobacter freundii | Enterobacter cloacae | Escherichia coli | Klebsiella pneumoniae | Pseudomonas aeruginosa | |
| ≤0.03 | — | — | 3/4 (75.0) | 1/1 (100.0) | — |
| 0.06 | — | — | 8/8 (100.0) | 0/1 (0.0) | — |
| 0.12 | 1/1 (100.0) | — | 40/48 (83.3) | 15/17 (88.2) | — |
| 0.25 | 1/1 (100.0) | 6/6 (100.0) | 27/30 (90.0) | 11/12 (91.7) | — |
| 0.5 | 5/6 (83.3) | 2/4 (50.0) | 12/12 (100.0) | 25/30 (83.3) | — |
| 1 | 1/1 (100.0) | 7/7 (100.0) | 3/4 (75.0) | 27/29 (93.1) | — |
| 2 | — | 1/1 (100.0) | 5/5 (100.0) | 6/6 (100.0) | — |
| 4 | — | 1/3 (33.3) | 1/1 (100.0) | 0/2 (0.0) | 1/4 (25.0) |
| 8 | — | — | 4/4 (100.0) | — | 7/9 (77.8) |
| 16 | — | — | — | — | 1/3 (33.3) |
| 32 | — | — | — | — | 3/3 (100.0) |
| >32 | — | 0/1 (0.0) | — | 0/1 (0.0) | 6/9 (66.7) |
Patients could have >1 pathogen. Microbiological outcomes were categorized as eradication or presumed eradication of the baseline pathogen (i.e., favorable response), persistence or persistence with increasing MIC (i.e., unfavorable response), or indeterminate. Data pooled from the ceftazidime-avibactam arms of the microbiologically evaluable (ME) population of the phase 2 trial in patients with cIAI (NCT00752219 [39]) and the extended ME populations of the phase 3 trials in patients with cIAI (RECLAIM 1 and 2 [NCT01499290 and NCT01500239] and RECLAIM 3 [NCT01726023] [40, 43]), cUTI (RECAPTURE 1 and 2 [NCT01595438 and NCT01599806] [41]), cIAI or cUTI caused by ceftazidime-nonsusceptible pathogens (REPRISE [NCT01644643] [42]), and NP, including VAP (REPROVE [NCT01808092] [44]). Intra-abdominal cultures required an invasive procedure and were obtained only when clinically indicated; therefore, microbiological responses for patients with cIAI were presumed based on clinical outcomes. The empty row indicates the approved ceftazidime-avibactam-susceptible clinical breakpoint of MIC ≤8 mg/liter applied to both Enterobacteriaceae and P. aeruginosa (8, 9).
The low rate of clinical failures is a key limitation in interpreting the PK/PD targets used for PTA analyses; however, the overall high clinical/microbiological success rates are broadly consistent with the PK/PD analyses using joint target attainment criteria in supporting the assigned ceftazidime-avibactam-susceptible breakpoint (≤8 mg/liter) against both Enterobacteriaceae and P. aeruginosa. Moreover, surveillance data confirm that the MIC cutoff of ≤8 mg/liter separates ceftazidime-avibactam-resistant MBL-carrying isolates from those without known ceftazidime-avibactam resistance mechanisms (3, 47, 48). These breakpoints define ≥90% of Enterobacteriaceae and P. aeruginosa infections from contemporary global surveillance, including key antibiotic-resistant subpopulations, as susceptible to ceftazidime-avibactam (3–6, 28–34).
Data availability.
Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the U.S. and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.
ACKNOWLEDGMENTS
We thank all investigators and patients involved in the ceftazidime-avibactam clinical trial program. Thanks also to Boudewijn L. M. de Jonge for providing additional INFORM Enterobacteriaceae data.
Medical writing support was provided by Mark Waterlow at Prime, Knutsford, Cheshire, United Kingdom, and was funded by AstraZeneca and Pfizer.
The ceftazidime-avibactam phase 2 and 3 clinical studies (clinicaltrials.gov NCT00752219, NCT01499290, NCT01500239, NCT01726023, NCT01595438, NCT01599806, NCT01644643, and NCT01808092) were originally sponsored by AstraZeneca and are now sponsored by Pfizer. The population PK analyses and the global (excluding the United States) INFORM surveillance program were funded by AstraZeneca. AstraZeneca's rights to ceftazidime-avibactam were acquired by Pfizer in December 2016.
We had full access to all study data and take responsibility for the integrity of the data and the accuracy of the data analysis.
W.W.N. is a former employee of AstraZeneca and current shareholder in AstraZeneca. G.G.S. is a former employee of and shareholder in AstraZeneca and current employee of Pfizer. P.N., H.B., A.W., and S.D. are former employees of and current shareholders in AstraZeneca. K.Y. is a former contractor for AstraZeneca. M.M. is a former employee of Wright Dose Ltd., Altrincham, United Kingdom, which received funding from AstraZeneca for support and assistance with the population PK analyses; she is also a shareholder in AstraZeneca. T.R. is an employee of and shareholder in Allergan. I.A.C. is a former employee of and current shareholder in Allergan.
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