Ceftazidime

Detailed information

Assessment report from 2016

Assessment report for Zavicefta (ceftazidime, avibactam) 28 April 2016, EMA/CHMP/377887/2016.

Hazard

Persistence OECD308: "Total system half-life (DT₅₀): 2.31 days high organic matter sediment (HOM); 9.99 days low organic matter sediment (LOM). Mineralisation (Day 93): 9.3% HOM, 31.2% LOM. One significant degradation product, M3, >10% of radioactivity in both the HOC and LOC systems. DT₅₀ values = 20.8 and 101 days in the HOC and LOC, respectively. In the LOC a second metabolite M1, had a calculated half-life of 118 days. Mass Balance (day 14) : 88.6% to 112.2% (LOC); 87.2% to 98.4% (HOC). [...] It was noted that the study on ceftazidime transformation in water/sediment systems (OECD 308) showed that both main transformation products M1 and M3 are very persistent as the DT₅₀ values in the low organic content (LOC) system are higher than 60 days. As a result, Zavicefta should be considered as very persistent."

Bioaccumulation OECD107: "LogD_ow< -2.20 (pH5), LogD_ow < -2.21 (pH7), LogD_ow < -2.17 (pH9). The log D values for ceftazidime are < 4.5 at all environmentally relevant pHs, therefore screening for PBT is not required as this does not meet the criteria for classification as a PBT compound."

Chronic toxicity: There are NOEC for 3 trophic levels, lowest NOEC for blue green algae 13 microg/L.

Risk

The risk, PEC/PNEC, calculated from data in the assessment report from a European perspective:

PEC_surfacewater, refined = 0.06 microg/L.

PNEC = Lowest NOEC, 13 microg/L/10 (Assessment Factor (AF) for 3 chronic studies) = 1.3 microg/L.

PEC/PNEC_surfacewater = 0.046. "Unlikely to represent a risk to the aquatic environment."

Assessment report from 2020

Assessment report for Zavicefta 17 September 2020, EMA/543616/2020.

"The Phase II Tier A assessment for ceftazidime was assessed during the initial marketing authorisation procedure, and therefore the results in table 2 are copied from the previous assessment report."

PEC/PNEC_surfacewater = 0,085. "Unlikely to represent a risk to the aquatic environment. [...] The issues with the calculation of the Fpen for avibactam and ceftazidime and the prevalence/consumption data have been resolved in the last revision of the environmental risk assessment. The PEC_surfacewater for both substances are now accepted, as well as the prevalence/consumption data."

"For the calculation of the PNEC of all three compartments, an assessment factor (AF) of 10 is used. The risk quotient (RQ) for all compartments are under the action limit (table 2), therefore a Tier B is not triggered. However, in the water-sediment study greater than 10% of the applied radioactivity was associated with the sediment phase, therefore the effect of ceftazidime on the sediment dwelling organism Chironomus riparius was investigated in Tier B.

Phase II Tier B, ceftazidime
The Tier B study on sediment-water toxicity in Chironomids has been assessed previously: LOEC (28d) >100 mg/kg dw, NOEC 100 mg/kg dw, recalculated to standard sediment: NOEC_{standard sediment} 303 mg/kg, and using an AF of 10, results in a PNEC of 3030 μg/kg. The calculation of the PEC_sediment is slightly different from the previous application (the Kp_susp is calculated using the weight fraction organic carbon in susp. solids (default value) and the K_OC rather than using the Kd value). The CHMP considered the use of the weight fraction organic carbon in susp. solids (default value) and the K_OC rather than using the Kd value in the calculation of the Kp_susp acceptable. The RQ_sediment is 0.00043, which is under the action limit of 1 and no further testing is required."

Comment on Fass environmental information

Ceftazidime has different classifications on fass.se. According to Lif (the trade association for the research-based pharmaceutical industry in Sweden) the various pharmaceutical companies compile environmental information for their active substances based on internal studies and published data. Based on data, which may thus differ between different pharmaceutical companies, the companies assess the environmental risk with guidance from “Environmental classification of pharmaceuticals at www.fass.se – Guidance for pharmaceutical companies 2012”. The Swedish Environmental Institute (IVL) reviews the assessment but does not have the task of coordinating/harmonizing environmental information from different pharmaceutical companies for the same active substance.

Fass environmental information for Fortum

Fass environmental information for Fortum (ceftazidime) (downloaded 2023-11-17). The environmental information for ceftazidime (anhydrous) was produced by the company GlaxoSmithKline for Fortum, Fortum®.

Fara

Persistence: "34% primary (parent) degradation in 14 days (OECD 302B). Ceftazidime is not readily biodegradable nor inherently biodegradable. The phrase “Ceftazidime is potentially persistent” is thus chosen."

Bioaccumulation: "Log D_ow = -3.07 at pH 7.4 (TAD 3.02)."

Toxicity: There are NOEC for 3 trophic levels, lowest NOEC for blue green algae 13 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2019. PEC/PNEC = 0.00953 which gives the risk insignificant.

Fass environmental information for Zavicefta

Fass environmental information for ceftazidime from Zavicefta (avibactam, ceftazidime) from from Pfizer (downloaded 2023-11-17).

Hazard

Persistence: "Ceftazidime total system DT₅₀ values in the high and low organic carbon sediment systems were 2.3 and 10 days, respectively. At the end of the 93-day long study, the active substance was no longer detectable in the low organic sediment, and only trace amounts (0.4%) were detected in the high organic sediment. Therefore, the substance is degraded in the environment."

Bioaccumulation: Log D = -2.21 at 7 (guideline OECD 107).

Chronic toxicity: There are data for 3 trophic levels, most sensitive blue-green alga NOEC = 13 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2021. PEC/PNEC = 0.00206 which gives the risk insignificant.

Antibiotic resistance

Studies have shown that even low concentrations of antibiotics in the environment can contribute to antibiotic resistance and therefore as little as possible should end up in our environment.

For antibiotics in general, it is recommended that these drugs are used as restrictively as possible without risking the patient's health.