Pharmacoepidemiology of Ceftazidime-Avibactam Use: A Retrospective Cohort Analysis of 210 US Hospitals

Abstract

Background: Ceftazidime-avibactam has in vitro activity against some carbapenem-resistant gram-negative infections (GNIs), and therefore may be a useful alternative to more toxic antibiotics such as colistin. Understanding ceftazidime-avibactam uptake and usage patterns would inform hospital formularies, stewardship, and antibiotic development.

Methods: A retrospective cohort study assessed inpatient encounters in the Vizient database. Ceftazidime-avibactam and colistin administrations were categorized into presumed empiric (3 consecutive days of therapy or less with qualifying exclusions) versus targeted therapy (≥4 consecutive days of therapy) for presumed carbapenem-resistant GNIs. Quarterly percentage change (QPC) using modified Poisson regression and relative change in frequency of targeted ceftazidime-avibactam to colistin encounters was calculated. Factors associated with preferentially receiving targeted ceftazidime-avibactam versus colistin were identified using generalized estimating equations.

Results: Between 2015 quarter (q) 1 and 2017q4, ceftazidime-avibactam was administered 21 215 times across 1901 encounters. Inpatient prescriptions for ceftazidime-avibactam increased from 0.44/10 000 hospitalizations in 2015q1 to 7.7/10 000 in 2017q4 (QPC, +11%; 95% CI, 10-13%; P < .01), while conversely colistin prescriptions decreased quarterly by 5% (95% CI, 4-6%; P < .01). Ceftazidime-avibactam therapy was categorized as empiric 25% of the time, targeted 65% of the time, and indeterminate 10% of the time. Patients with chronic kidney disease were twice as likely to receive targeted ceftazidime-avibactam versus colistin (RR, 2.02; 95% CI, 1.82-2.25), whereas those on dialysis were less likely to receive ceftazidime-avibactam than colistin (RR, 0.71; 95% CI, .61-.83).

Conclusions: Since approval in 2015, ceftazidime-avibactam use has grown for presumed carbapenem-resistant GNIs, while colistin has correspondingly declined. Renal function drove the choice between ceftazidime-avibactam and colistin as targeted therapy.

Keywords: carbapenem resistance; ceftazidime-avibactam; novel beta-lactamase inhibitors; ram-negative resistance.

Figure 1.

Encounter flowsheet. ^aList of select antibiotics in which ceftazidime-avibactam was prescribed: amikacin, aztreonam, ceftazidime, chloramphenicol, colistin, imipenem/cilastatin, minocycline, ampicillin/sulbactam, ticarcillin/clavulanate/tobramycin, ertapenem, tigecycline, fosfomycin, doripenem, ceftazidime-avibactam, ceftolozane-tazobactam, piperacillin-tazobactam, ciprofloxacin, cefepime, meropenem, levofloxacin, gentamicin. ^bPatients non–mutually exclusive as encounters who received concomitant ceftazidime-avibactam and colistin are not removed and they may have multiple encounters across different therapy categories and multiple encounters within a therapy category. Abbreviation: q, quarter.

Figure 2.

Cumulative hospital uptake was evaluated by quarter. Blue bars represent a summation of the number of hospitals eligible to prescribe each quarter based on prescriptions in prior quarters. In quarter 1 of 2015, there were a total of 5 hospitals that had prescribed ceftazidime-avibactam and this increased to 93 in quarter 4 of 2017. The overlaying dark-red trend line represents the percentage of hospitals that actually prescribed in each respective quarter out of the total that had prescribed at least 1 dose in prior quarters (n = 93). A total of 210 hospitals reported any pharmacy data during the study period. Abbreviation: q, quarter.

Figure 3.

Ceftazidime-avibactam utilization by quarter. A, After the removal of all encounters with diagnosis codes for cystic fibrosis quarterly rates in prescriptions for ceftazidime-avibactam and colistin were evaluated. Using Poisson regression, the number of ceftazidime-avibactam prescriptions increased by 11.2% (95% CI, 9.6–12.7%; P < .01), and over the same time period, colistin decreased by 5.1% (95% CI, 4.3–6.0%; P < .01). The red line represents colistin prescription, the light blue line represents ceftazidime-avibactam, the dark-blue lines represent trend lines, and gray shading represents CIs. B, Targeted encounters for ceftazidime-avibactam and colistin were summed to quantify the overall treatments for carbapenem-resistant gram-negative infections. The percentage of carbapenem-resistant gram-negative infections treated with ceftazidime-avibactam increased from 3% in 2015q1 to 53% in 2017q4, a QPC of 12.6% (95% CI, 10.6–14.5%). Abbreviations: CI, confidence interval; q, quarter; QPC, quarterly percentage change.

Figure 4.

A, Percentage of targeted ceftazidime-avibactam encounters that were prescribed as monotherapy and combination therapy with concomitant antibiotics having at least 4 consecutive days of overlap with ceftazidime-avibactam therapy. Monotherapy (36%), 1 concomitant antibiotic (30%), 2 concomitant antibiotics (19%), 3+ concomitant antibiotics (15%). B, Distribution of concomitant antibiotics. Carbapenems (38%), aminoglycosides (22%), colistin (14%), fluoroquinolones (15%), tigecycline (11%), aztreonam (4%), minocycline (3%), ampicillin/sulbactam (2%). Cefepime, ceftazidime, and piperacillin-tazobactam not included as concomitant antibiotics as they are unlikely to maintain in vitro activity in carbapenem-resistant gram-negative infections. ^aCarbapenems (meropenem, doripenem, imipenem, ertapenem). ^bAminoglycosides (amikacin, gentamicin, tobramycin). ^cFluoroquinolones (ciprofloxacin and levofloxacin).