Published online November 30, 2007
PEDIATRICS Vol. 120 No. 6 December 2007, pp. 1255-1259 (doi:10.1542/peds.2007-0630)
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ARTICLE

Stability of Antibiotics in Portable Pumps Used for Bronchial Superinfection: Guidelines for Prescribers

Nicolas Arlicot, PhDa, Gaël Y. Rochefort, PhDb, Deborah Schlecht, PhDb, Fabien Lamoureux, PharmDa, Sophie Marchand, MDc and Daniel Antier, PharmD, PhDa,b

Departments of a Pharmacy
c Pediatrics, University Hospital, Tours, France
b Laboratory of Physiopathology of the Arterial Wall (LABPART), University François Rabelais, Tours, France


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. The aims of this study were (1) to collect data on the stability of antibiotics in portable pumps for the treatment of bronchial superinfection in patients with cystic fibrosis and (2) to provide guidelines for prescribers.

METHODS. The stability over 72 hours, in portable pumps stored at 35°C, of piperacillin plus tazobactam, ticarcillin plus clavulanic acid, cefsulodin, cefepime, and aztreonam was checked at 3 different concentrations. Stability was assessed through visual examination, pH measurements, and direct measurements of drug concentrations by using high-performance liquid chromatography. All parameters were measured at time 0, time 0 plus 24 hours, and time 0 plus 72 hours.

RESULTS. Degradation rates for penicillin plus β-lactamase inhibitor combinations remained <10% at time 0 plus 24 hours for all drugs, but the rate for piperacillin reached 12% for the highest concentration tested. The cephalosporins cefepime and cefsulodin had significant respective degradation rates of 18% and 28% at time 0 plus 24 hours and 60% and 68.5% at time 0 plus 72 hours, which were linked to the storage temperature. Aztreonam seemed to be stable over 72 hours.

CONCLUSIONS. This work provides data on drug stability that were lacking, allowing recommendations for physicians to optimize the safety and efficacy of antibiotic treatment of patients with cystic fibrosis. Piperacillin plus tazobactam and ticarcillin plus clavulanic acid infusions must be limited to 24 hours, and patients receiving cefepime or cefsulodin must wear a cold pack close to the ambulatory drug-delivery device during the infusion.

Key Words: antibiotic use • cystic fibrosis • infusion device • guidelines • efficacy

Abbreviations: CF—cystic fibrosis • HPLC—high-performance liquid chromatography

Cystic fibrosis (CF), an inherited disease with an autosomal recessive mechanism, is characterized by the accumulation of thick mucus in the lungs. The lungs of patients with CF are colonized and infected by specific bacteria from an early age,1 mainly Pseudomonas aeruginosa,2 which is responsible for chronic endobronchial infections and consequently respiratory function decline, with direct effects on the quality of life and survival times for patients with CF.3 These infections are usually treated with intravenously administered antibiotics (combinations of a β-lactam with an aminoglycoside or fluoroquinolone),4 especially in cases of acute pulmonary exacerbations. In this context, continuous infusion is an efficient means of administering antibiotics, to limit the selection of multidrug-resistant strains of pathogens.5 This is consistent with the use of portable elastomeric infusion systems worn under clothing on the patient's belt. Under those conditions, drugs are exposed to a storage temperature close to body temperature. However, published stability data related to antibiotics in elastomeric pumps provide little information on temperatures of >25°C. Therefore, the purpose of this study, managed in collaboration with the Department of Pediatrics, University Hospital (Tours, France), was to assess under real conditions the physiochemical stability of antibiotics prescribed frequently for patients with CF, as packaged in elastomeric infusion pumps, and thus to provide guidelines for physicians to optimize their clinical practice.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Preliminary Study
The stability of drugs in aqueous solution can be influenced by drug concentrations, storage temperatures, solvents, and medical infusion devices. Stability data for antibiotics currently prescribed to treat bronchial superinfection with P aeruginosa in patients with CF, diluted in saline solution according to local protocols and administered through portable pumps, were collected from Internet databases (PubMed and Medline) and the Handbook on Injectable Drugs, 10th Edition,6 and then classified according to the aforementioned parameters.

Experimental Protocol
Information collected from the literature (see below) showed a major lack of data on the stability of antibiotics in portable pumps, particularly regarding the storage temperature. We checked on the stability in infusors of most antibiotics prescribed for cases of superinfection with P aeruginosa in patients with CF, stored at 35 ± 1°C, which is the average temperature measured with a thermal probe positioned in the pump reservoir over 24 hours under real conditions.7 Drugs were obtained through a hospital pharmacy, including piperacillin plus tazobactam (Tazocilline; Wyeth-Lederlee Pharmaceuticals, Blois, France), ticarcillin plus clavulanic acid (Claventin; GlaxoSmithKline, Heppignies, Belgium), cefsulodin (Pyocefal; Takeda, Puteaux, France), cefepime (Axepim; Bristol-Myers/Squibb, Rueil-Malmaison, France), and aztreonam (Azactam, Sanofi-Aventis, Paris, France).

Drug Concentrations
The stability of each drug was tested at 3 different concentrations extrapolated from local therapeutic protocols, that is, the lowest usual concentration decreased by 20% (concentration 1), the mean clinically used concentration (concentration 2), and the highest usual concentration increased by 20% (concentration 3) (Table 1).


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  		TABLE 1 Antibiotic Concentrations Studied

 
Stability Controls
Infusors (n = 6 per concentration for each antibiotic) were filled with antibiotics dissolved in sterile water and diluted to the correct concentration with saline solution, in a 240-mL elastomeric infusion system (Baxter Healthcare, Deerfield, IL), and were then stored in the dark at 35 ± 1°C for 72 hours. Stability parameters were measured as follows: (1) a visual examination was performed with a white background to detect particles, precipitate, and color changes; (2) pH was measured by using a pH meter with a glass-body electrode (Knick model 761; Knick Laboratory, Berlin, Germany); and (3) drug residual concentration measurements were performed at room temperature through high-performance liquid chromatography (HPLC) with a PerkinElmer Series 200 HPLC system (PerkinElmer, Courtaboeuf, France). All reagents for HPLC analysis were purchased from Merck (Darmstadt, Germany), Carlo Erba (Milan, Italy), and Prolabo (Paris, France). Experimental conditions for antibiotic assays and references are summarized in Table 2. Visual examinations, pH measurements, and concentration measurements were performed at time 0, time 0 plus 24 hours, and time 0 plus 72 hours.


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  		TABLE 2 Experimental Conditions of Antibiotic Assays by HPLC

 
Statistical Analyses
For both pH and drug concentration measurements, analysis of variance followed by the Student t test, with significance levels set at 1% and 5%, was performed. The link between absorbance and drug concentrations was assessed by using the Spearman correlation coefficient. All results are expressed as means ± SDs.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Preliminary Study
Data from the literature on the stability of the most commonly prescribed antibiotics administered with elastomeric infusion systems to patients with CF are summarized in Table 3. Published studies mainly reported the stability of antibiotics over 24 hours at 25°C. No data on cefsulodin packaged in a pump were available, and the range of antibiotic concentrations tested did not always match prescriptions for patients with CF.


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  		TABLE 3 Published Data on Stability of Antibiotics in Elastomeric Medical Infusion Devices, According to Drug Concentrations, Duration of Study, and Storage Temperature

 
Experimental Study
Visual Examination
At time 0 plus 24 hours, the color of both cefsulodin and ticarcillin plus clavulanic acid solutions turned from orange to light brown and the color of the cefepime solution turned from light brown to dark brown. At time 0 plus 72 hours, a sensitive progression of color intensity was noted for the aforementioned antibiotics. However, neither precipitates nor color changes were noted during the study for all other antibiotic solutions.

pH Measurements
The pH of each incubated sample was measured at time 0, time 0 plus 24 hours, and time 0 plus 72 hours for all antibiotics, and data were plotted (Fig 1). The only significant (P < .05) change over 72 hours was observed for cefepime solutions, which exhibited an increase in pH from 4.4 (time 0) to 7.2 (time 0 plus 72 hours).


Figure 1
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  		FIGURE 1 Evolution of pH at 35 ± 1°C over 72 hours, at the middle concentration tested (concentration 2), for solutions of cefepime ({diamondsuit}), cefsulodin (•), piperacillin plus tazobactam ({blacktriangleup}), ticarcillin plus clavulanic acid ({blacksquare}), and aztreonam (x). All values are mean ± SD of 3 repeated measurements for each infusor (symbols without SD bars indicate values with SDs smaller than the symbol size).

 
Antibiotic Concentration Measurements
The degradation rates for marketed penicillin plus β-lactamase inhibitor combinations (piperacillin plus tazobactam and ticarcillin plus clavulanic acid) remained <10% at time 0 plus 24 hours for concentrations 1, 2, and 3, except for the highest concentration of piperacillin, which reached a significant (P < .05) degradation rate of 12%. The losses of both piperacillin and clavulanic acid were positively correlated (P < .05) with drug concentrations. Tazobactam was very stable throughout the study, because its degradation rate never exceeded 5% at any concentration, and ticarcillin displayed degradation rates of 10% to 16% at time 0 plus 72 hours for concentrations 1, 2, and 3 (Fig 2A). Except for aztreonam, which was stable over 72 hours at concentrations 1, 2, and 3 under the conditions of the study (Fig 2B), all drugs showed new peaks, presumably reflecting degradation products, on chromatograms obtained at time 0 plus 72 hours. None of the new peaks interfered with the initial peaks of β-lactams.


Figure 2
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  		FIGURE 2 Residual concentrations of antibiotics in portable pumps maintained at 35 ± 1°C over 72 hours, at the middle concentration tested (concentration 2), for the penicillins and β-lactamase inhibitors piperacillin ({blacktriangleup}), tazobactam ({triangleup}), ticarcillin ({blacksquare}), and clavulanic acid ({square}) (A) and the cephalosporins cefepime ({diamondsuit}) and cefsulodin (•) and aztreonam (x) (B). All values are mean ± SD of 3 repeated measurements for each infusor.

 
Regarding the cephalosporins' stability, significant (P < .01) degradation rates of 18% and 28% at time 0 plus 24 hours and 60% and 68.5% at time 0 plus 72 hours were observed for cefepime and cefsulodin, respectively (Fig 2B). The degradation rate of cefsulodin did not change in a statistically significant way according to the concentration, and no positive correlation between cefepime concentrations and the respective degradation rates was established.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Increases in resistant strains of P aeruginosa oblige clinicians to optimize treatment efficacy in cases of acute pulmonary exacerbations for patients with CF. Pharmacodynamic and pharmacoeconomic studies are clearly in favor of administration through continuous infusion of time-dependent antibiotics such as β-lactams,8–11 particularly because the same therapeutic effect can be achieved with a lower daily dose of drug.10 Those factors explain the increasing use of portable pumps, which improve patients' quality of life by allowing ambulatory therapy and also reduce home nursing services.

However, for efficacy and safety of continuous antibiotic administration, the drug must remain stable throughout the duration of the infusion. Parameters influencing drug stability in solution are numerous,6 and physicochemical studies that mimic real conditions of drug infusion are the best approach to guarantee drug stability. Most studies with β-lactams in elastomeric pumps were performed over 24 hours at a maximal storage temperature of 25°C.12–14 In the present study, we considered the stability of antibiotics at 35°C, the mean temperature measured in pumps maintained under real conditions of use. This measurement contradicts another study15 that reported that the temperature of the antibiotic solution in a portable device would not increase above 27°C. However, those authors used motorized, portable, infusion pumps placed in an external pouch. Viaene et al16 used the same type of elastomeric system as we did, and they estimated the temperature of the drug solutions in the pump as close to body temperature (ie, ~37°C).

According to our results, the stability of the ticarcillin plus clavulanic acid mixture at 35°C over 24 hours in the elastomeric pump is ensured for the concentration ranges of 12 to 150 mg/mL and 0.8 to 10 mg/mL, respectively. For the piperacillin plus tazobactam mixture, the slight 5% degradation of the β-lactamase inhibitor at time 0 plus 72 hours must be appreciated, with attention to the significant concentration- and time-correlated degradation of piperacillin from 12% at time 0 plus 24 hours to 33% at time 0 plus 72 hours for the highest concentration tested (90 mg/mL). This degradation is temperature- and time-dependent, because piperacillin was reported to be stable when maintained at 25°C versus 35 ± 1°C.16 Prescribers must be aware that the efficacy of piperacillin plus tazobactam solutions in portable pumps might be compromised if infusion is prolonged beyond 24 hours.

Cephalosporins are known for being chemically less stable than penicillins in aqueous solutions.17 Indeed, we observed that both cefsulodin and cefepime exhibited ~20% losses after 24 hours, reaching 60% degradation at time 0 plus 72 hours. These data match those of a previous study16 that reported that a 50 mg/mL cefepime solution maintained at 37°C had a degradation rate of 10% after only 13 hours. It is noteworthy that the degradation of these 2 cephalosporins was not correlated with the drug concentration, which is in agreement with other published data.18 However, the stability of both cefepime and cefsulodin seemed to be tightly linked to the storage temperature, because other studies concluded that cephalosporin solutions could be kept for 2 days at 24°C, conserving 90% of their initial drug concentrations.14 To guarantee the efficacy of continuous infusion of cefepime and cefsulodin with a portable pump, the use of a cold pack placed in the pump carrying case seems to be the best option, because cold packs have already proved their efficacy for 24 hours with a ceftazidime solution.19

Data from the literature suggest that β-lactam degradation induces breakdown products for which safety is not clearly established and compounds identified as toxic (such as pyridine) result from degradation of the β-lactam ring of cephalosporins.15 Such a statement reinforces the need for physicians to care about the stability of prescribed drugs.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Major information from this study concerns 2 points. First, penicillin plus β-lactamase inhibitor mixtures, such as piperacillin plus tazobactam and ticarcillin plus clavulanic acid, seemed to be stable enough for continuous infusion up to 24 hours. Second, both cefepime and cefsulodin required temperature regulation, which could be obtained by using a cold pack close to the ambulatory drug-delivery system. These results are additional guidelines to support a pharmacologically safe approach to antibiotic administration through elastomeric portable infusion pumps.


   FOOTNOTES
 
Accepted May 31, 2007.

Address correspondence to Daniel Antier, PharmD, PhD, Department of Pharmacy, University Hospital of Tours, 2 Blvd Tonnellé, 37044 Tours Cedex, France. E-mail: antier{at}med.univ-tours.fr

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Ratjen F, Döring G. Cystic fibrosis. Lancet. 2003;361 :681 –689[CrossRef][Web of Science][Medline]
  2. Husson MO. Microbiological aspects of mucoviscidose [in French]. Antibiotiques. 2002;(4) :1 –59
  3. Britto MT, DeVellis RF, Hornung RW, DeFriese GH, Atherton HD, Slap GB. Health care preferences and priorities of adolescents with chronic illnesses. Pediatrics. 2004;114 :1272 –1280[Abstract/Free Full Text]
  4. French Society of Microbiology. Reference Frame in Medical Microbiology [Référentiel en Microbiologie Médicale; in French]. 2nd ed. Montmorency, France: 2M2; 2004:52 –55
  5. Garrafo R. Pharmacodynamic basis of IV administration of β-lactam antibiotics by continuous perfusion: optimization of antibacterial activity for Gram-negative bacteria [in French]. Antibiotiques. 2002;(4) :23 –28
  6. Trissel LA. Handbook on Injectable Drugs. 10th ed. Bethesda, MD; American Society of Hospital Pharmacists; 2003
  7. De Calbiac P, Lamoureux F, Pourrat X, et al. Treatment of bronchial superinfections: data related to stability of antibiotics in portable pumps. Thérapie. 2006;61 :139 –144[Medline]
  8. Rappaz I, Decosterd LA, Bille J, et al. Continuous infusion of ceftazidime with a portable pump is as effective as thrice-a-day bolus in cystic fibrosis children. Eur J Pediatr. 2000;159 :919 –925[CrossRef][Web of Science][Medline]
  9. Frei CR, Burgess DS. Continuous infusion β-lactams for intensive care unit pulmonary infections. Clin Microbiol Infect. 2005;11 :418 –421[CrossRef][Web of Science][Medline]
  10. Grant EM, Kuti JL, Nicolau DP, Nightingale CH, Quintiliani R. Clinical efficacy and pharmacoeconomics of a continuous-infusion piperacillin-tazobactam program in a large community teaching hospital. Pharmacotherapy. 2002;22 :471 –483[CrossRef][Web of Science][Medline]
  11. Karchmer AW. Cephalosporins. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill-Livingstone; 2000:274 –288
  12. Zhang Y, Trissel LA. Stability of piperacillin and ticarcillin in autodose infusion system bags. Ann Pharmacother. 2001;35 :1360 –1363[Abstract/Free Full Text]
  13. Xu QA, Trissel LA, Saenz CA, Ingram DS, Williams KY. Stability of three cephalosporin antibiotics in autodose infusion system bags. J Am Pharm Assoc. 2002;42 :428 –431[CrossRef]
  14. Trissel LA, Xu QA. Stability of cefepime hydrochloride in autodose infusion system bags. Ann Pharmacother. 2003;37 :804 –807[Abstract/Free Full Text]
  15. Sprauten PF, Beringer PM, Louie SG, Synold TW, Gill MA. Stability and antibacterial activity of cefepime during continuous infusion. Antimicrob Agents Chemother. 2003;47 :1991 –1994[Abstract/Free Full Text]
  16. Viaene E, Chanteux H, Servais H, Mingeot-Leclercq MP, Tulkens PM. 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). Antimicrob Agents Chemother. 2002;46 :2327 –2332[Abstract/Free Full Text]
  17. Baldwin JE, Schofield CJ. In: Page MI, ed. The Chemistry of β-Lactams. London, England: Blackie Academic and Professional; 1992:1 –78
  18. Baririan N, Chanteux H, Viaene E, Servais H, Tulkens PM. Stability and compatibility study of cefepime in comparison with ceftazidime for potential administration by continuous infusion under conditions pertinent to ambulatory treatment of cystic fibrosis patients and to administration in intensive care units. J Antimicrob Chemother. 2003;51 :651 –658[Abstract/Free Full Text]
  19. Couldry R, Sanborn M, Klutman NE, et al. Continuous infusion of ceftazidime with an elastomeric infusion device. Am J Health Syst Pharm. 1998;55 :145 –149[Abstract/Free Full Text]
  20. Marunaka T, Maniwa M, Matsushima E, et al. High-performance liquid chromatographic determination of new β-lactamase inhibitor and its metabolite in combination therapy with piperacillin in biological materials. J Chromatogr. 1988;431 :87 –101[CrossRef][Web of Science][Medline]
  21. Reed MD, Stern RC, Yamashita TS, Ackers I, Myers CM, Blumer JL. Single-dose pharmacokinetics of cefsulodin in patients with cystic fibrosis. Antimicrob Agents Chemother. 1984;25 :579 –581[Abstract/Free Full Text]
  22. Pilkiewicz FG, Remsburg BJ, Fisher SM, Sykes RB. High-pressure liquid chromatographic analysis of aztreonam in sera and urine. Antimicrob Agents Chemother. 1983;23 :852 –856[Abstract/Free Full Text]
  23. Zambon Biomedica Laboratory. Guidelines for the Administration of Drugs Using the Home Pump/Home Pump Eclipse Disposable Elastomeric Infusions Systems [information sheet]. Bresso, Italy: Zambon Biomedica Laboratory; 2000
  24. Baxter Laboratory. Drug Stability in Intermate SV50, SV100, and SV200 [information sheet]. Deerfield, IL: Baxter Laboratory; 2000
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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