Stability of reconstituted solutions of ceftazidime for injections: an HPLC and CE approach

Farina, A.; Porrà, R; Cotichini, V.; Doldo, A.

doi:10.1016/s0731-7085(99)00057-6

Cited by 29 publications

(19 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As illustrated in Tables 1 and 2, (i) we confirm that the stability of CAZ is significantly better at low temperature, i.e., at 4°C rather than 22°C or 33°C (3)(4)(5), and that (ii) the production of P is unavoidable regardless of the operational conditions and (iii) the absolute amount of P produced per day of continuous infusion is significantly lower in model 2 (BID regimen) than in model 1 (ODD regimen). Finally, an acceptable compromise needs to be reached between a bioavailable and expected amount of delivered CAZ and the amount of P inevitably coinjected into the patient.…”

Section: Discussionsupporting

confidence: 66%

See 1 more Smart Citation

How To Minimize Toxic Exposure to Pyridine during Continuous Infusion of Ceftazidime in Patients with Cystic Fibrosis?

Bourget¹,

Amin

Dupont³

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Ceftazidime is particularly efficient against Pseudomonas aeruginosa in cystic fibrosis patients. Thus, the spontaneous production of pyridine, which is a toxic product, raises some concern. Our aim was to examine the kinetics of degradation of ceftazidime in portable infusion pumps either at 4°C, 22°C, or 33°C and to propose some recommendations in order to reduce the pyridine exposure. Two administration models were studied in vitro. In model 1, we administered 12 g of ceftazidime infused over 23 h (once-daily infusion) compared to 6 g infused over 11.5 h in model 2 (twice-daily regimen). Samples were collected at 0 h and then every 4 and 2 h after the shaping of portable infusion pumps in models 1 and 2, respectively. Both ceftazidime and pyridine were analyzed using an ultraviolet high-performance liquid chromatograph. Production of pyridine is highly depending on the temperature. The in situ production of pyridine per day of treatment decreases at a ratio close to 1/6 and 1/3 between 33°C and 4°C in models 1 and 2, respectively. Regardless of the conditions, the production of pyridine is significantly lower in model 2, whereas the total delivery amount of ceftazidime is significantly higher at 4°C and 33°C compared to that in model 1. According to a the precautionary principle, these findings lead to three major recommendations: (i) exposing a solution of ceftazidime to over 22°C should be strictly avoided, (ii) a divided dose of 6 g over 11.5 h instead of a once-daily administration is preferred, and (iii) infusion should be administered immediately after reconstitution.

show abstract

Section: Discussionsupporting

confidence: 66%

“…This is also true for other beta-lactam analogs (2). Thus, the spontaneous production of pyridine (P), which is a toxic product, raises some concern (3)(4)(5). The chemical structures of ceftazidime and its main degradation product are depicted in Fig.…”

mentioning

confidence: 99%

How To Minimize Toxic Exposure to Pyridine during Continuous Infusion of Ceftazidime in Patients with Cystic Fibrosis?

Bourget¹,

Amin

Dupont³

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Drugs were considered stable when concentrations were ≥95 % of the values obtained immediately after drug dilution, without mixing (Farina et al, 1999). Aminophylline, was stable at all time periods evaluated (Table I), as it was previously published, regardless of ceftazidime addition.…”

Section: Stability Of Ceftazidime and Aminophylline Solutions By Hplcsupporting

confidence: 59%

“…However, the same drug mixture at 0 hour presented ceftazidime MIC increase of 15 and 3.9 fold for E. coli and P. aeruginosa, respectively. The hydrolysis of ceftazidime triggered by the basic pH was probably enhanced by the 37 °C maintained throughout the MIC tests (Farina et al, 1999). Since the human body maintains the same temperature, it is likely that degradation continues after drug infusion.…”

Section: Discussionmentioning

confidence: 99%

Biological and physicochemical stability of ceftazidime and aminophylline on glucose parenteral solution

Santos

Knirsch

Stephano

et al. 2012

Braz. J. Pharm. Sci.

View full text Add to dashboard Cite

Ceftazidime is a broad spectrum antibiotic administered mainly by the parenteral route, and it is especially effective against Pseudomonas aeruginosa. The period of time in which serum levels exceed the Minimum Inhibitory Concentration (MIC) is an important pharmacodynamic parameter for its efficacy. One of the forms to extend this period is to administer the antibiotic by continuous infusion, after prior dilution in a Parenteral Solution (PS). The present work assessed the stability of ceftazidime in 5% glucose PS for 24 hours, combined or not with aminophylline, through High Performance Liquid Chromatography (HPLC). The physicochemical evaluation was accompanied by in vitro antimicrobial activity compared MIC test in the 24-hour period. Escherichia coli and Pseudomonas aeruginosa were the microorganisms chosen for the MIC comparison. The HPLC analysis confirmed ceftazidime and aminophylline individual stability on PS, while the MIC values were slightly higher than the mean described in the literature. When both drugs were associated in the same PS, the ceftazidime concentration by HPLC decreased 25% after 24 hours. Not only did the MIC values show high loss of antibiotic activity within the same period, but also altered MIC values immediately after the preparation, which was not detected by HPLC. Our results indicate that this drug combination is not compatible, even if used right away, and that PS might not be the best vehicle for ceftazidime, emphasizing the importance of the MIC evaluation for drug interactions. Ceftazidima é um antimicrobiano administrado por via parenteral, que apresenta amplo espectro de ação, principalmente contra Pseudomonas aeruginosa. O tempo em que a concentração sérica de ceftazidima permanece acima da concentração mínima inibitória (MIC) é um importante parâmetro farmacodinâmico para a determinação da eficácia antimicrobiana e pode ser potencializado através da utilização de infusão contínua em soluções parenterais (PS). Este artigo visa a avaliar a estabilidade da ceftazidima em solução de glicose 5%, na presença e na ausência do fármaco aminofilina, através de cromatografia líquida de alta eficiência HPLC e MIC durante o período de 24 horas. Os microorganismos selecionados para a determinação do MIC foram Escherichia coli e Pseudomonas aeruginosa. Os ensaios em cromatógrafo líquido confirmaram a estabilidade dos fármacos ceftazidima e aminofilina quando são individualmente associados em PS, enquanto os valores de MIC ficaram maiores que os valores encontrados na literatura. Quando ambos os fármacos foram associados na mesma solução parenteral a concentração de ceftazidima obtida por HPLC diminuiu 25% depois de 24 horas. Os valores de MIC mostraram maior decaimento da atividade antimicrobiana neste mesmo período e também valores de MIC alterados nas soluções preparadas no tempo zero, decaimento este que não foi detectado em HPLC. Os resultados indicaram incompatibilidade na associação dos fármacos em PS, enfatizando a importância dos resultados de MIC para interações de fármacos.

show abstract

“…While little is known about the safety of the ethanal derivative, pyridine is a well-known toxic, and the level of its release needs therefore to be accurately determined. This has already been studied by several authors (10,11,32,42), but we considered it useful to reexamine this issue in order to unambiguously establish the link between drug instability and pyridine release in the projected conditions of clinical use. Our results not only confirm clearly this relationship but also demonstrate that pyridine release exceeds the limit considered acceptable by the U.S. Pharmacopeia (39) if the drug is kept at 37°C for more than a few hours.…”

mentioning

confidence: 96%

Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

Viaene

Chanteux

Servais

et al. 2002

Antimicrob Agents Chemother

178

123

View full text Add to dashboard Cite

The stability of antipseudomonal ␤-lactams in concentrated solutions was examined in view of their potential administration by continuous infusion with external pumps (for intensive care patients) or with portable pumps carried under clothing (for cystic fibrosis patients). Aztreonam (100 g/liter), piperacillin (128 g/liter, with tazobactam), and azlocillin (128 g/liter) remained 90% stable for up to more than 24 h at 37°C (mezlocillin [128 g/liter] was stable at 25°C but not at 37°C). Ceftazidime (120 g/liter), cefpirome (32 g/liter), and cefepime (50 g/liter) remained 90% stable for up to 24, 23.7, and 20.5 h at 25°C but only for 8, 7.25, and 13 h at 37°C, respectively. The control of temperature therefore appears to be critical for all three cephalosporins that cannot be recommended for use in portable pumps carried under clothes for prolonged periods for reasons of stability. Cefpirome and cefepime solutions developed an important color change (from light yellow to dark red) upon exposure when stored at 30°C or higher. Degradation of ceftazidime was accompanied by the liberation of pyridine which, at 37°C, was in excess of what is allowed by the U.S. Pharmacopeia, i.e., 1.1 mg/liter, after 8 and 12 h for drug concentrations of 12 and 8.3%, respectively. Imipenem and meropenem are too unstable (10% degradation at 25°C after 3.5 and 5.15 h, respectively) to be recommended for use by continuous infusion. Faropenem, examined in comparison with imipenem and meropenem, proved as stable as aztreonam or piperacillin.␤-Lactams are one of the most typical antibiotic classes for which the pharmacodynamic data, collected in vitro, as well as in animal studies, clearly indicate a potential advantage of a continuous infusion over the more conventional, discrete mode of administration (see references 6, 22, 23, 38, and 41 for reviews). Accordingly, several clinical trials have been initiated over the last half-decade, most notably in difficult-to-treat situations such as suspected gram-negative infections in critically ill patients (3), severe infections in intensive care patients (8,16,21,24,37), septicemia (1), severe sepsis (20), and cystic fibrosis (29,40). Yet, as clearly pointed out by one of the first promoters of the continuous infusion of ␤-lactams (6), this mode of administration, through programmable pumps or other similar devices, requires the drug to remain sufficiently stable in solution over the projected duration of the infusion. In a previous study (30), we examined the stability of ceftazidime in solution and found it to be critically dependent on the temperature within the 20 to 37°C range (68 to 99°F). This sets clear limitations on the potential use of ceftazidime by continuous infusion if administrations every 24 h are contemplated without periodic changes of the solutions. Chemical considerations suggest that the stability of the main ␤-lactams currently registered for human medicine use may vary to a meaningful extent. Unfortunately, these variations, and their consequences as far as continuous infu...

show abstract

Stability of reconstituted solutions of ceftazidime for injections: an HPLC and CE approach

Cited by 29 publications

References 8 publications

How To Minimize Toxic Exposure to Pyridine during Continuous Infusion of Ceftazidime in Patients with Cystic Fibrosis?

How To Minimize Toxic Exposure to Pyridine during Continuous Infusion of Ceftazidime in Patients with Cystic Fibrosis?

Biological and physicochemical stability of ceftazidime and aminophylline on glucose parenteral solution

Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

Contact Info

Product

Resources

About