Simplified Aztreonam Dosing in Patients with End-Stage Renal Disease: Results of a Monte Carlo Simulation

The manufacturer-recommended aztreonam dosing for patients with creatinine clearance values of <10 ml/min/1.73 m² is complex. It is not known whether simpler posthemodialysis dosing administered once daily or thrice weekly can reliably achieve pharmacodynamic goals.

ABSTRACT

The manufacturer-recommended aztreonam dosing for patients with creatinine clearance values of <10 ml/min/1.73 m² is complex. It is not known whether simpler posthemodialysis dosing administered once daily or thrice weekly can reliably achieve pharmacodynamic goals. We found that 1 or 2 g administered once daily after hemodialysis had >90% probability of target attainment up to MICs of 4 or 8 mg/liter, respectively. Thrice-weekly dosing should generally be avoided, except in nonsevere infections with MICs of ≤0.5 mg/liter.

TEXT

For more than 3 decades, aztreonam has continued to serve an important role in the treatment of Enterobacteriaceae and Pseudomonas infections in patients with significant β-lactam allergies (1). In addition, aztreonam may be a therapeutic option for increasingly common multidrug-resistant Gram-negative bacilli, given its unique activity against Ambler class B metallo-β-lactamases (2). To improve patient outcomes, dosing should be optimized based on pharmacodynamic parameters; updates to the interpretative breakpoints for aztreonam by the Clinical and Laboratory Standards Institute (CLSI) are based on the likelihood of achieving ≥50% free-drug time above the MIC (fT_MIC) (3–5). Furthermore, the manufacturer's recommendations for aztreonam dosing in patients with creatinine clearance (CL_CR) values of <10 ml/min/1.73 m² state that the dose should be 25% of the normal dose administered with the same interval; this typically results in a dose of 250 mg or 500 mg administered every 8 h, with a supplemental dose of 125 mg or 250 mg administered after hemodialysis (HD) in severe infections (1, 6). However, it is not known whether simpler, post-HD dosing once daily or thrice weekly can reliably achieve pharmacodynamic goals, given that the half-life of aztreonam is prolonged in renal dysfunction (1, 6). Therefore, we conducted a Monte Carlo simulation (MCS) using a population pharmacokinetic model developed with data from patients with normal or impaired renal function, including patients with CL_CR values of <10 ml/min/1.73 m², to determine the probability of target attainment (PTA) with simplified aztreonam dosing (once daily or thrice weekly) (6).

The aztreonam population pharmacokinetic model involving 11 male volunteers with CL_CR values of <10 ml/min/1.73 m², based on the Cockcroft-Gault formula, was described previously (6–8). In those studies, aztreonam serum concentrations were determined at standard times after a single 1-g dose; patients did not receive dialysis during the sampling period (7, 8). MCS was conducted as described previously (6). Briefly, 1,000 concentration-time profiles for patients with CL_CR values of <10 ml/min/1.73 m² were simulated from the aztreonam population pharmacokinetic model using nonlinear mixed-effects modeling (NONMEM) (version 7.3; ICON Development Solution, Hanover, MD) (6). Body weight was a significant covariate in the population pharmacokinetic model. In the MCS, the body weight for each of the 1,000 patients was sampled based on the body weight distribution (mean, 71.4 kg; standard deviation [SD], 11.7 kg) for patients with CL_CR values of <10 ml/min/1.73 m² (7, 8). Three dosing strategies (1 g or 2 g once daily or 2 g thrice weekly [days 1, 3, and 5], using a 30-min intravenous infusion for all regimens) were used in the simulation. Aztreonam concentrations were assumed to be zero following HD. The fT_MIC values on day 1 for 1-g or 2-g once-daily dosing and on days 1 to 7 for 2-g thrice-weekly dosing were determined for MICs ranging from 0.03 mg/liter to 32 mg/liter, and pharmacodynamic targets of 50% and 60% fT_MIC were evaluated. The PTAs for each dosing regimen at each MIC were then calculated as the fractions of 1,000 subjects achieving 50% and 60% fT_MIC. The 50% fT_MIC was used for the primary analysis, given that this is the target used by the CLSI for interpretive breakpoints and in vitro data found this target to be associated with a 1-log₁₀ unit decrease in bacterial counts at 24 h (3–5, 9). Given the limited underlying data, however, we also assessed the target of 60% fT_MIC as the most conservative sensitivity analysis; this target has been associated with a 2-log₁₀ unit reduction in bacterial counts at 24 h (9). To evaluate safety, the daily mean maximum concentration (C_max) and the area under the concentration-time curve from 0 to 24 h (AUC_0–24) for the regimen with the highest dose (2 g once daily) were evaluated. A plasma protein-binding value of 42.1% was used for all simulations and was presumed to be dose independent (10, 11).

Table 1 and Fig. 1 include the results of the MCS for the PTAs for aztreonam at 1 g or 2 g administered once daily or 2 g administered thrice weekly, stratified by bacterial MIC. Aztreonam at 2 g or 1 g once daily (timed after HD for patients receiving HD) provided the best PTAs, with 96.2% chances of achieving 50% fT_MIC for pathogens with MICs of 8 mg/liter or 4 mg/liter, respectively. Aztreonam at 2 g administered thrice weekly performed the worst; 90% PTA was achieved only with a MIC of ≤0.5 mg/liter. The daily mean C_max and AUC_0–24 values for the highest dose (2 g once daily) were 82.7 mg/liter and 1,138 mg · h/liter, respectively.

TABLE 1.

Probability of target attainment with simplified aztreonam dosing in patients with CL_CR values of <10 ml/min/1.73 m²

Aztreonam dose and MIC (mg/liter)a	PTA (%)
	50% fTMIC	60% fTMIC
1 g once daily
0.03	100	100
0.06	100	100
0.125	100	100
0.25	100	100
0.5	100	99.9
1	99.9	99.4
2	99.4	97.2
4	96.2	87.4
8	67	44.7
16	3.6	0.8
32	0	0
2 g once daily
0.03	100	100
0.06	100	100
0.125	100	100
0.25	100	100
0.5	100	100
1	100	99.6
2	99.7	99.2
4	99.2	97.4
8	96.2	85.7
16	69.8	43.7
32	2.9	0.9
2 g thrice weekly (days 1, 3, and 5)
0.03	99.7	98.4
0.06	99.4	96.5
0.125	98.3	93.4
0.25	95.8	87.7
0.5	90.9	78.8
1	82.1	66
2	66.9	46.5
4	43.1	24.2
8	14.3	5.6
16	0.7	0.1
32	0	0

^aIt is assumed that, for patients requiring HD, all doses (including daily doses) are administered immediately after HD.

FIG 1.

Probability of target attainment (50% fT_MIC) with simplified aztreonam dosing in patients with CL_CR values of <10 ml/min/1.73 m². The dosing scheme was 1 g every 24 h, 2 g every 24 h, or 2 g thrice weekly (days 1, 3, and 5). For patients requiring HD, it was assumed that all doses (including daily doses) were administered immediately after HD.

Modeling and simulation have been widely utilized in drug development to support dose selection, development decisions, and regulatory submission and labeling (12, 13). Our results indicate that aztreonam dosing for patients with CL_CR values of <10 ml/min/1.73 m² can be greatly simplified while still achieving pharmacodynamic goals for susceptible isolates. Aztreonam breakpoints from the CLSI recommend that Enterobacteriaceae strains with MICs of ≤4 mg/liter and Pseudomonas strains with MICs of ≤8 mg/liter be considered susceptible, based on dosing of 1 g every 8 h or 2 g every 8 h, respectively (4). The European Committee on Antimicrobial Susceptibility Testing considers strains with MICs of ≤1 mg/liter susceptible for both Enterobacteriaceae and Pseudomonas, regardless of aztreonam dosing (14). Thrice-weekly post-HD dosing in patients with end-stage renal disease has been shown to achieve pharmacodynamic goals, based on population pharmacokinetic studies and MCS, for cefazolin, ceftazidime, and cefepime (15–18). Relative to those agents, however, there is a greater proportion of nonrenal elimination of aztreonam and thus thrice-weekly dosing of aztreonam is unlikely to be effective unless the pathogen MIC is ≤0.5 mg/liter (1). Notably, in an international database containing data from multiple sites and time periods, only 79 of 3,191 P. aeruginosa isolates had aztreonam MICs of ≤0.5 mg/liter; therefore, it is unlikely that thrice-weekly dosing of aztreonam would be appropriate for P. aeruginosa (19). We also suggest avoiding thrice-weekly dosing for neutropenic patients and patients with severe or high-inoculum infections due to Enterobacteriaceae, even when the MIC is confirmed to be ≤0.5 mg/liter. A dose of 2 g daily should be preferred when possible because of the greater PTAs, especially for P. aeruginosa isolates, given higher CLSI breakpoints and higher MIC distributions (4, 19). A dose of 1 g daily may be adequate for susceptible Enterobacteriaceae strains, based on current CLSI breakpoints (4).

In addition to the pharmacodynamics, the potential toxicity of the studied regimens should be considered. Aztreonam is generally well tolerated, with the most common adverse effects typically being injection site reactions, gastrointestinal adverse effects, and rash (20). The mean daily C_max and AUC_0–24 for the most intensive dosing regimen we evaluated (2 g once daily) were similar to exposures with FDA-approved regimens (i.e., 204 mg/liter and 1,336 mg · h/liter, respectively) (1, 21). Therefore, the tested regimens are not expected to be associated with toxicity risks greater than normal.

This study has some limitations. It was based on a small population of otherwise healthy male volunteers, and elimination of the drug during HD was not determined in the source pharmacokinetic studies (7, 8). To mitigate this limitation and to provide the most conservative PTA, we assumed that no drug would remain at the end of HD. With the use of 1 or 2 g daily for organisms with MICs of 4 or 8 mg/liter, respectively, the PTA for the sensitivity analysis (60% fT_MIC) fell just below 90%. Thus, we suggest that 2 g once daily be used for most patients and that clinicians exercise caution if the MIC is equivalent to 8 mg/liter and the patient either is neutropenic or is being treated for a severe or high-inoculum infection.

In conclusion, we found that aztreonam dosing can be greatly simplified for patients with CL_CR values of <10 ml/min/1.73 m² by using 1 to 2 g administered once daily (timed after HD on HD days). Thrice-weekly dosing of aztreonam after HD should generally be avoided, with the exception of nonsevere infections due to Enterobacteriaceae strains with MICs of ≤0.5 mg/liter.