TY - JOUR
AU - Cheam, Dat, Boon
AB - Abstract Purpose This article reviews the literature concerning ceftazidime stability and potential for toxicity from pyridine (a degradation product) in the light of decades of apparent safe use of this antibiotic when given by continuous i.v. infusion but recent changes in regulatory body/manufacturer advise a need to change infusion devices more frequently. Summary In the outpatient setting, ceftazidime is ideally administered by continuous i.v. infusion because of its short half-life and lack of post-antibiotic effect. While continuous i.v. infusion provides the optimal pharmacokinetic/pharmacodynamic profile, the frequency with which infusion devices need to be changed is critical to the practicality in the outpatient setting, especially where trained staff are required to visit the patient in their home to change the device. The rate of ceftazidime degradation (and pyridine formation) is temperature, concentration, and solvent dependent. By using the lowest effective dose (guided by pathogen minimum inhibitory concentration [MIC] so as to achieve a blood concentration ≥ 4 × MIC over the whole dosage interval), keeping ceftazidime concentration ≤ 3%, using 0.9% sodium chloride injection as diluent and maintaining temperature between 15–25°C when connected to the patient, the amount of pyridine formed over a 24-hour period can be minimized and toxicity prevented. When pathogen MIC dictates that > 6 g ceftazidime/day is required, alternative antibiotics should be considered and/or greater attention paid to temperature and concentration of the infusion solution. Conclusion Ceftazidime can be used safely and effectively via continuous i.v. infusion in the outpatient setting with once-daily changes of infusion device provided the concentration and temperature of the infusion solution is controlled. In this way, more frequent changes of infusion device (that increase the risk of blood-borne infection and reduce the practicality of continuous i.v. infusion in the home) can be avoided. ceftazidime, continuous infusion, continuous i.v. infusion, pyridine, toxicity KEY POINTS Ceftazidime is hydrolyzed to pyridine, a potential toxin and hydrolysis increases with temperature and initial ceftazidime concentration. Changing infusion device more frequently than every 24 hours increases the risk of blood-borne infection, increases cost and reduces practicality of continuous i.v. infusion in the home. Ceftazidime infusion devices can be safely changed once every 24 hours by ensuring ceftazidime concentration is ≤ 3%, temperature is kept between 15–22°C and 0.9% sodium chloride injection is the solvent. For decades, ceftazidime has been administered by continuous i.v. infusion using a variety of devices, including portable elastomeric infusion pumps. Administration by portable pumps allows patients to be discharged from hospital earlier, thereby reducing costs and risks of acquiring and spreading hospital-borne pathogens. The infusion devices are typically changed once daily, thereby facilitating a relatively normal lifestyle for patients who are only required to be at home at one set time each day. While ceftazidime is one of several third-generation cephalosporins, it has particular activity against Pseudomonas aeruginosa and consequently, patients with cystic fibrosis and bronchiectasis are the major patient groups who have received this therapy because they are prone to infections from this gram-negative pathogen by virtue of the inability to clear tenacious secretions from the airways. Ceftazidime, like most other beta-lactam antibiotics, is cleared from the body primarily via glomerular filtration and has a short half-life (~1.8 h) in patients with normal renal function.1 Ceftazidime’s antibacterial activity does not continue to increase as concentration increases—maximal kill rates occur at concentrations about 4 times the minimum inhibitory concentration (MIC) and hence ceftazidime (like other beta lactams) is not a “concentration-dependent” antibiotic.2 Beta lactams do not possess any useful post-antibiotic effect, especially against gram-negative bacteria that resume multiplying soon after the drug concentration falls below the MIC. As a consequence of these two properties, beta lactams are described as “time-dependent” killers and the goal of therapy should be to rapidly attain a concentration of 4 times the MIC and to maintain this concentration for the duration of the dosage treatment period.3 Using this model, lower total ceftazidime daily doses are needed with continuous i.v. infusion than with intermittent infusions—maintaining plasma concentrations ≥ 4 mg/L with intermittent (every 8 hours) infusions requires approximately 75 mg/kg/day while continuous i.v. infusion requires only 20 mg/kg/day.4 The MIC for ceftazidime against P. aeruginosa varies but it will likely be reported as “sensitive” whenever the MIC is ≤ 8 mg/L—the value chosen by the European Committee on Antimicrobial Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI).5,6 If the pathogen MIC is 8 mg/L, the laboratory would report “sensitive” but, using the above model, the target plasma concentration should be 32 mg/L and this would require a dose of approximately 600 mg/kg/day every 8 hours or 160 mg/kg/day by continuous i.v. infusion (assuming linear kinetics). For a 70 kg patient this would require 14 g every 8 hours or 11.2 g/day by continuous i.v. infusion—a much higher than “normal” dose. It is worth noting the ceftazidime MIC values chosen by EUCAST/CLSI are premised on plasma concentrations achieved by giving 1 g every 6 hours or 2 g every 8 hours (i.e., targeting the actual MIC, rather than 4 times the MIC). While ceftazidime distributes into tissues well, the concentration at sites distant from blood is typically lower than that in plasma and it could therefore be argued that higher doses would be required to allow a concentration of 4 × MIC to be achieved in infected tissues. In particular, the ceftazidime concentration in sputum has been reported as ~15% of mean serum concentration in a population of cystic fibrosis patients who were given 100 mg/kg/day by continuous i.v. infusion.7 A variety of infusion devices have been used over the decades and one of the most popular has been the elastomeric device. This device is sterile prior to loading with ceftazidime solution, which is done in an aseptic facility to maintain sterility, typically either in the hospital pharmacy or commercial premises. The infusion solution is forced under pressure into a bladder and the elastic nature of the bladder provides the energy to subsequently propel the solution through the i.v. line into the bloodstream. The rate of flow is determined primarily by resistance within the tubing that connects to the i.v. line and this is dependent on temperature, viscosity of the liquid, and diameter of the tubing. Elastomeric devices are not precise—they “nominally” deliver the dose over a set period (typically 24 h) but the manufacturer advise a 10%–12.5% variability. This has been observed in clinical studies where the whole 24 hour dose has been delivered in a shorter time (resulting in higher early plasma concentrations followed by lower concentrations later in the infusion period) or only part of the dose being delivered in 24 hours (resulting in lower plasma concentrations over the whole period).8,9 The manufacturer of Infusor (Baxter Healthcare, Old Toongabbie, NSW) advise a 2.3% variation in flow rate should be expected with every 1°C above or below a narrow range (31.1°C–33.3°C) and that flow rate will be approximately 10% higher when the less viscous 0.9% sodium chloride injection is used instead of 5% dextrose (the solution used to calibrate the device). Ceftazidime degradation would be greatly retarded if the infusion device could be maintained at 4°C but one study of the device showed only 65% of the volume was delivered over 24 hours at this temperature.9 Computerized infusion devices are available and while these should more accurately deliver the desired volume of solution over the entire dosage interval, we are not aware of any studies that have compared such devices with the more popular and cheaper elastomeric devices for ceftazidime delivery in the home. Drug delivery should be more reliable at lower temperatures with devices that use a direct mechanical means (e.g., peristaltic pump) to propel the solution through the tubing rather than relying on elastic forces. Hence there is a prospect that ceftazidime solutions could be kept at low temperatures that would retard hydrolysis such that pyridine formation is minimal. We are not aware of any device that keeps solutions at a low temperature at this time. It would be important that they are not unduly bulky, and battery performance is critical—both issues already identified as important to patients.10 In our hospital, ceftazidime has been used for decades in adults with infective exacerbations of bronchiectasis when P. aeruginosa is grown from sputum/bronchoscopy samples. Initial treatment is typically 1 g every 6–8 hours, but when the patient is clinically stable, and a suitable intravenous access is available, treatment continues as an outpatient using 3 g ceftazidime by continuous i.v. infusion using elastomeric pumps, for a total period of ~14 days. The 24 hour infusion devices are changed at the same time each day in the patient’s home by a trained registered nurse. Anecdotally, there have been no observed toxicities from this regimen and eradication of P. aeruginosa has been achieved in some (though not all) patients; data have not been collected and examined systematically. Recently, the Australian Therapeutic Guidelines handbook (a widely-used guide in Australasia) reduced the recommended change time from 24 to 12 hours for elastomeric devices containing ceftazidime. Reasons given for this change were (a) concerns over ceftazidime stability and (b) potential for toxicity from degradation products, and these concerns were informed by 3 publications.11-13 These data have also informed the very recent decision by one of the 2 major Australian commercial suppliers of ceftazidime infusion devices (Baxter Healthcare) who now advise a maximum storage time of 6 hours for solutions containing ≤ 60 mg/mL at a storage temperature of 25°C. This manufacturer also advises that an alternative is to administer ceftazidime over a shorter (2.5 h) period every 12 hours, but this fails to maintain plasma concentrations greater or equal to 4 times the MIC for the whole dosage interval as well as making early discharge from hospital less practicable. The other major Australian commercial supplier (Slade Health, Mount Waverley, Victoria, Australia) has not changed its advice at this time (to change infusion devices every 24 h). In the UK, the Fortum Summary of Product Characteristics14 advises that ceftazidime solution is stable at 25°C for 9 hours; hence infusion devices are routinely changed every 8 hours (personal communication, Royal Brompton Hospital). There is thus considerable variability and confusion surrounding ceftazidime stability and potential for pyridine toxicity, and a review appears warranted. Ceftazidime degradation Ceftazidime, like most other beta-lactams, is relatively unstable and readily hydrolyzed to microbiologically inactive degradation products. The rate of degradation is pH and temperature dependent and, interestingly, has also been shown to be concentration dependent.15-17 Fubara et al.15 demonstrated that as the initial ceftazidime concentration increased, the rate of destruction of the ceftazidime molecule also increased and that the rate of destruction was not slowed as ceftazidime was consumed. Thus, while the catalytic moiety was not identified, it was not affected by hydrolysis of the parent molecule. This has implications for both ceftazidime dose and concentration (and hence also for the volume of solvent used). The ceftazidime molecule incorporates a pyridine ring that is released during hydrolysis and sufficient pyridine is produced with “usual doses” that it has been detected by researchers by its characteristic sulphide odour.15-17 The maximum pyridine dose a patient could receive from 1 g ceftazidime (if it completely degraded) is approximately 145 mg). Other degradation products have been identified, including an ethanal derivative and a –∆2 ceftazidime isomer but pyridine appears to be the major one formed at temperatures ≤ 37°C.15,17,18 The potential for pyridine toxicity has been the major concern that has resulted in the advice to change infusion devices more frequently. Pyridine toxicity Much of the data on pyridine toxicity has resulted from atmospheric/environmental exposure and/or from rare cases of ingestion; we are not aware of any published cases of pyridine toxicity resulting from ceftazidime administration, especially via continuous i.v. infusion. Acute poisoning can be fatal; we found one case report on Toxnet of accidental oral ingestion of ~120 g resulting in fatality. But what constitutes a “safe dose” has not been established. The minimum oral dose that might result in fatality has been reported as 500 mg/kg.19 Chronic pyridine exposure has been reported to cause morbidity (including hepatotoxicity) though much of this data is derived from animal studies. In a 1943 study of pyridine’s potential as an anticonvulsive, 5 patients were given ~2 g/day pyridine orally for ~30 days and hepatorenal syndrome was reported in two patients, of whom one died.20 There are no human safety data for pyridine when administered intravenously, either as a bolus or by continuous i.v. infusion, but continuous i.v. infusion may be safer because maximum pyridine concentrations would be lower than for an equivalent “bolus” dose since pyridine is cleared as it is administered. Pyridine is cleared from the body via several routes including kidney and lung. Because ceftazidime doses are typically reduced in patients with renal impairment, pyridine exposure and toxicity would thus be mitigated in patients with renal impairment. Recent publications suggest pyridine exposure when ceftazidime is given via continuous i.v. infusion is approximately 50–500 mg/day; however, the higher amounts are difficult to reconcile or confirm because of limitations in the published data and assumptions about the temperature the devices would be exposed to over any 24-hour period.9,11,13 For 500 mg pyridine to be produced, ~3.5 g ceftazidime needs to be completely degraded and for this to occur, the infusion device would need to contain a large dose of ceftazidime (i.e., ≥ 10 g) and be exposed to elevated temperatures for prolonged periods. When doses of ceftazidime ≤ 6 g/day are used and the temperature of the infusion device is kept below body temperature, it appears that less than 100 mg pyridine is produced and, because of the apparent lack of toxicity over decades of use, this would appear to constitute a safe dose. This amount would appear to be a realistic “standard” against which the acceptability of ceftazidime administration by continuous i.v. infusion should be measured. Some authors have used pharmacopoeial standards such as the U.S. Pharmacopeia (USP) or European Medicines Agency (EMA) limits as the benchmark for toxicity but, because these limits are set for good manufacturing practices, they are inappropriate for this toxicological purpose.9,11 Other sources of pyridine Virtually all citizens of developed countries are exposed to pyridine every day from the atmosphere and/or from their diet. The Toxnet database advises that small amounts of pyridine are present in cigarette smoke (16–40 mcg in one cigarette), including side-stream smoke, and also in fried bacon and chicken, boiled beef, Beaufort cheese, roasted barley and coffee, canned sweetcorn, mangoes, and soybeans. The same database also advises pyridine is a by-product of shale oil production and is an allowed food additive in the United States, where it is used in ice-cream (0.02–0.12 ppm), baked goods (0.4 ppm), candy (0.4 ppm), and non-alcoholic beverages (1 ppm). It is unlikely that patients receiving ceftazidime via continuous i.v. infusion would benefit by reducing exposure from these “environmental” sources because the doses from such sources are relatively low and the evidence for toxicity from such doses is lacking. Pyridine is widely used as a solvent in the production of pharmaceuticals and hence small amounts are routinely administered to patients as a consequence of pyridine residues. The limits set by both the EMA and USP for residual pyridine is 2 mg/day but, as noted above, this limit is not meant to define the “safe” human dose. Rather, this limit is set by regulatory bodies in recognition of the difficulty in completely eliminating pyridine from pharmaceuticals. The EMA astutely notes that “…since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible [our italics] to meet product specifications, good manufacturing practices or other quality-based requirements.” The 2 mg/day pyridine limit is virtually unattainable by all ceftazidime dosage regimens (especially when administered by continuous i.v. infusion) due to residual “contamination” combined with ceftazidime degradation after dissolving. One study found ~4 mg pyridine was present (after 3 h at 37°C) in the vial when 1 g ceftazidime was dissolved in 3 mL water.18 Another study showed ~11 mg pyridine was present in devices containing 6 g/100 mL ceftazidime immediately after dissolution and this increased with refrigerated storage to 26 mg after 7 days and to 53 mg after 14 days.21 Pyridine production also varies with the type of infusion device and diluent.12 Using a freshly prepared solution of 40 g/L ceftazidime, Favetta et al.13 found 0.43 mg pyridine was present when 240 mL of 0.9% sodium chloride injection was used in an infusor but 10 mg was present when 110 mL of 5% dextrose injection was used in an ultraflow device. It is improbable this variation occurred from the ceftazidime vials (since the same vials were used for all) and hence it raises the possibility that pyridine was present in the dextrose solution or the ultraflow device, or that the presence of dextrose or other components in the ultraflow device accelerates ceftazidime degradation. Minimizing ceftazidime degradation and pyridine formation There are two concerns resulting from ceftazidime degradation, the first being loss of the active moiety (and hence reduced antimicrobial activity), which could be addressed by increasing the initial ceftazidime dose in a similar way pharmaceutical companies are allowed an “overage” to allow for loss during storage (the upper limit for ceftazidime in USP 29 monograph is 120%). However, because ceftazidime degradation is concentration dependent, this is an imperfect solution. Using ≥ 90% limit on ceftazidime stability as the “standard,” the time taken to fall to this value has varied in different studies (depending on temperature, solvent and concentration) from 8 hours to 1.5 days.9,11,12,16-18 It appears that attention to these factors can guarantee ceftazidime concentration exceeds 90% for 24 hours. The second issue is the potential for toxicity from degradation products, especially pyridine. Strategies to reduce exposure to pyridine and ensure adequate ceftazidime exposure Dose of ceftazidime. One of the major advantages of administering ceftazidime via continuous i.v. infusion is that lower doses are needed than if administered via intermittent infusion. Continuous i.v. infusion avoids unnecessary high concentrations while ensuring the concentration stays above the target of ~4 × MIC of pathogen for the entirety of the dosage interval. In order to avoid unnecessarily high doses of ceftazidime (and hence limit pyridine exposure), it is important to know the pathogen MIC which will then define the target concentration. Assuming all pathogens have the highest MIC (consistent with the “sensitive” descriptor) means unnecessarily high ceftazidime doses and unnecessarily large amounts of pyridine are administered to patients whenever the actual MIC is lower. Once the pathogen MIC is available, individualized loading and maintenance doses can be estimated from published values of Volume of Distribution (Vd) and clearance (estimated from the Cockroft and Gault equation). These calculations are well within the scope of clinical pharmacists/pharmacologists, whose expertise should be readily available in developed countries where outpatient continuous i.v. infusion is practiced. Confirming and refining the dose estimates via occasional plasma ceftazidime concentration monitoring would likely enhance patient outcomes and potentially reduce the development of pathogen resistance. The modest costs of individualizing treatment could be justified by the savings associated with out-of-hospital treatment and from reduced ceftazidime use. Whenever the pathogen MIC approaches 8 mg/L, it would be wise to consider alternative antimicrobial agents because the ceftazidime dose required to achieve the target plasma concentration (32 mg/L) is ~160 mg/kg/day (corresponding to 11.2 g/day for a 70 kg patient). Indeed, it might be argued that the breakpoints used by CLSI and EUCAST to define “sensitive” (for P. aeruginosa) should be lowered in recognition of the need to achieve ~4 multiples of the MIC. If, however, ceftazidime is the only or best choice, greater attention should be paid to reduce pyridine formation via means listed below. Volume and type of solvent used. It has been observed that rate of degradation of ceftazidime increases as initial ceftazidime concentration increases.11,15,17 Concentration can be reduced by increasing the volume of diluent and hence the largest volume that is practical should be used, especially when higher ceftazidime doses are required. Maximum fill volumes for commonly used infusion devices are ~240 mL. For patient convenience there is an upper limit on infusion device volume, and this is likely approximately 500–1000 mL to facilitate patient mobility and to reduce the problem of fluid overload. If the infusion device maximum volume is less (e.g., 250 mL), then a final volume of 500 mL can be achieved by using 2 devices (each with half the required daily dose) connected to the patient via a dual-lumen intravenous line or alternatively via a Y-site connector. Several authors have noted an increase in pyridine formation when 5% dextrose solution is used instead of 0.9% sodium chloride injection.13,15,22 There are very few clinical situations where 5% dextrose injection would be advantageous, hence 0.9% sodium chloride injection should be used as diluent. Temperature of solution. There are competing interests with regard to the “ideal” temperature at which devices should be kept while they are worn by the patient. At lower temperatures, elastomeric infusion devices deliver less than the nominal ceftazidime dose but ceftazidime stability improves, while at body temperature, ceftazidime delivery is better but stability is impaired. The “ideal” temperature range for infusor device performance claimed by the manufacturer is 31.1°C–33.3°C, and they further advise a 2.3% reduction in flow volume for every 1°C below this range. Simplistically, increasing the dose in proportion to the lost volume would allow lower temperatures to be used but because the rate of ceftazidime degradation is also concentration dependent the effect of increasing the dose would also increase the rate of degradation. Current data suggest a temperature range of 15–22°C would allow for effective device performance while decreasing ceftazidime degradation by ~30% from that seen at 33°C. Once prepared, devices should be used as soon as possible and if storage is necessary, a monitored refrigerator/freezer should be employed. As noted earlier, approximately 11 mg pyridine might be expected in a 6 g/100 mL elastomeric pump as soon as it is prepared, but this will increase to 26 mg when stored at 4°C for 7 days.21 For this reason, all storage before use should be minimized. Pyridine production in frozen solutions is less (15 mg was found by the above authors after 14 days at −20°C) but infusion device performance (including maintenance of sterility) must not be affected by freezing. Maintaining a temperature range of approximately 15–22°C would necessitate insulation with or without cooler packs in warm climates and this temperature range is not possible if devices are kept under clothing, especially the bed clothes overnight. Insulated ‘bags’ worn around the waist are widely used and these should have capacity for the device/s to be surrounded by cold packs that should be changed whenever the temperature increases (that should be advised by portable temperature monitors). Timing of changes of the infusion device. Pyridine formation (and hence patient exposure) is lessened by limiting the time that ceftazidime solutions are exposed to higher temperatures. Bourget et al.10 showed that the daily pyridine exposure was reduced from 91.5 mg when 12 g ceftazidime was administered by continuous i.v. infusion over 24 hours (in a volume of 230 mL, kept at 33°C) to 60.8 mg when the same dose was divided into two (i.e., 6 g in 115 mL changed at 12 h). However, reducing the exposure by ~30 mg in this way comes at the cost of increased risk of microbial access to the bloodstream, increased costs of both infusion devices and staff, and decreased practicality of discharging patients to their own homes. In this same study, Bourget et al.10 found the effect of reducing the temperature from 33°C to 22°C reduced the amount of pyridine from 91.5 mg to 58.1 mg (when changed every 24 hours) and from 60.8 mg to 52.8 mg (when changed every 12 hours). Hence the benefit (limiting pyridine exposure) derived from reducing device temperature (to a value that would not appear challenging) exceeds the benefit from changing infusion devices more frequently. When larger doses are required due to higher pathogen MIC (or accelerated ceftazidime clearance), changing the infusion device every 12 (or less) hours remains an option but, because this option renders outpatient use less feasible, we recommend this be the last option. Discussion Authors, regulatory bodies, and manufacturers who have recommended more frequent changes of ceftazidime containing infusion devices based purely on theoretical concerns over pyridine toxicity have prosecuted their case poorly because they have neither established a safe (or toxic) dose of pyridine nor explored alternative means of reducing pyridine formation. We are not aware of any data suggesting pyridine toxicity has resulted from ceftazidime administration and while there can be no doubt that pyridine will cause toxicity at high doses, it appears very unlikely that this has occurred at doses administered when ceftazidime has been administered via continuous i.v. infusion. Nonetheless, it appears eminently reasonable to take steps to reduce ceftazidime degradation (and consequent pyridine formation) provided such steps do not compromise the practicality and safety of administering ceftazidime via continuous i.v. infusion. The following recommendations provide practical means whereby this can be achieved. Tailor ceftazidime dose to pathogen MIC and limit ceftazidime dose to 6 g/day by continuous i.v. infusion in ordinary circumstances. Use 0.9% sodium chloride injection as the solvent and use the largest infusion volume possible (consistent with patient convenience) especially when higher ceftazidime doses are needed. Ceftazidime concentration should be kept ≤ 3%. This might require 2 infusion devices running concurrently. Monitor and maintain infusion device temperatures between 15–22°C by use of insulation or other means. Change the infusion devices more frequently only when the above recommendations are insufficient to limit ceftazidime degradation and pyridine formation. Conclusion Ceftazidime can be used safely and effectively via continuous i.v. infusion in the outpatient setting with once-daily changes of infusion device provided the concentration and temperature of the infusion solution is controlled. In this way, more frequent changes of infusion device that increase the risk of blood-borne infection and reduce the practicality of continuous i.v. infusion in the home can be avoided. Disclosures The authors have declared no potential conflicts of interest. References 1. Paradis D , Vallée F , Allard S et al. Comparative study of pharmacokinetics and serum bactericidal activities o cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin . Antimicrob Agents Chemother. 1992 ; 36 : 2085 – 92 . Google Scholar Crossref Search ADS PubMed 2. McKinnon PS , Davis SL . 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Ceftazidime stability and pyridine toxicity during continuous i.v. infusion
JF - American Journal of Health-System Pharmacy
DO - 10.1093/ajhp/zxy035
DA - 2019-02-01
UR - https://www.deepdyve.com/lp/oxford-university-press/ceftazidime-stability-and-pyridine-toxicity-during-continuous-i-v-m0d8JSaW0N
SP - 200
VL - 76
IS - 4
DP - DeepDyve
ER -