A survey of the utilization of antipseudomonal betalactam therapy in cystic fibrosis patients

Pediatric Pulmonology 46:987–990 (2011) A Survey of the Utilization of Anti-Pseudomonal Beta-Lactam Therapy in Cystic Fibrosis Patients Jeffery T. Zobell, PharmD,1,2* David C. Young, PharmD,3 C. Dustin Waters, PharmD, BCPS,4 Krow Ampofo, MD,5 Jared Cash, PharmD, BCPS,1 Bruce C. Marshall, MD,6 Summary. The purpose of this study was to characterize the utilization of anti-pseudomonalbeta-lactam antibiotics in the treatment of acute pulmonary exacerbations (APE) among CysticFibrosis Foundation (CFF)-accredited care centers. An anonymous national cross-sectionalsurvey of CFF-accredited care centers was performed using an electronic survey tool (Survey-Monkey.com1). One hundred and twenty-one of 261 centers completed the survey (46%) rep-resenting 56% (14,856/26,740) of patients in the CFF Patient Registry. One hundred andnineteen of 121 (98%) respondents reported using beta-lactams for the treatment of APE.
Intermittent dosing regimens constituted 155/167 (93%) reported regimens, while extendedinfusions were 12/167 (7%). Ceftazidime was the most commonly utilized beta-lactam compris-ing 74/167 (44%) of all infusions (intermittent and extended) of which 70/74 (95%) were inter-mittent infusions. The majority of intermittent ceftazidime regimens (56/70; 80%) were at doseslower than CFF and European guidelines recommended doses. In conclusion, a great majorityof respondents use intermittent anti-pseudomonal beta-lactam antibiotics, with over half ofrespondents utilizing lower than guidelines recommended doses. While this is of concern, it isnot known if optimization of dosing strategies according to guidelines recommendations willresult in clinical benefit. Pediatr Pulmonol. 2011;46:987–990.
Key words: Pseudomonas aeruginosa; antibiotics; pulmonary exacerbations.
dosing regimens of each antipseudomonal beta-lactamutilized amongst CFF-accredited care centers is not Based on the recommendations from the Cystic known. The purpose of this study is to quantify the Fibrosis Foundation (CFF), acute pulmonary exacer-bations (APE) should be treated with two anti-pseudo-monal antibiotics with different mechanisms of actionto enhance antibacterial activity and reduce selection of 1Department of Pharmacy, Intermountain Primary Children’s Medical resistant organisms.1 The most common antibiotic classes used in combination to treat APE are beta- 2Intermountain Cystic Fibrosis Pediatric Center, University of Utah, Salt lactams and aminoglycosides with antipseudomonal 3College of Pharmacy, University of Utah, Salt Lake City, Utah.
Recently, a study was performed to quantify the prevalence of once-daily tobramycin (antipseudomonal Department of Pharmacy, Intermountain McKay-Dee Hospital Center, aminoglycoside) utilization at CFF-accredited care cen- ters across the United States, and to characterize the 5Division of Infectious Disease, University of Utah, Salt Lake City, Utah.
approaches used for APE amongst these institutions.2 6Cystic Fibrosis Foundation, Bethesda, Maryland.
The utilization of antipseudomonal beta-lactams [i.e.,aztreonam (actually a monobactam), cefepime, ceftazi- *Correspondence to: Jeffery T. Zobell, PharmD, Department of Phar- dime, doripenem, imipenem–cilastatin, meropenem, macy, Intermountain Primary Children’s Medical Center, 100 NorthMario Capecchi Drive, Salt Lake City, UT 84113 piperacillin–tazobactam, and ticarcillin–clavulanate] for APE is an area of question that has not been answeredin the literature. A wide variety of dosing strategies Received 29 November 2010; Revised 17 February 2011; Accepted 25 exist for antipseudomonal beta-lactams, including inter- mittent infusion (FDA approved vs. high dose) or extended infusion (i.e., infusion over 4 hr or continu- Published online 25 April 2011 in Wiley Online Library ously).1,3–9 However, the prevalence of utilization and utilization of each anti-pseudomonal beta-lactam in the WA.10 Differences between these regional groups (both treatment of APE among CFF-accredited care centers, for pediatric and adult centers) were determined by using and to characterize the dosing regimens used by these a Friedman’s test (non-parametric, two-way analysis of institutions in the treatment of APE.
variance; http://faculty.vassar.edu/lowry/VassarStats.html).
Differences between the size of centers who responded to the survey and those who did not respond to the surveywere also determined by using Mann–Whitney U-test This study was an anonymous national cross-sec- (non-parametric test for two-independent samples; http:// tional survey of CFF-accredited care centers in the faculty.vassar.edu/lowry/utest.html).
United States. Information was collected using anelectronic survey tool (SurveyMonkey.com1). Thestudy population consisted of 261 CFF-accredited pro- grams in the United States (117 pediatric programs, 96 The response rate to the survey was 46% (121/261 adult programs, and 48 combined pediatric and adult CFF-accredited care center sites). Of the 121 respond- ents, 80% were physicians (52 pediatric program direc- Upon receiving institutional review board approval, tors, 26 adult program directors, 12 pediatric/adult the survey was piloted internally by various providers program directors, seven center physicians). Respondent familiar with CF care before being sent to the CFF for demographic data are reported in Table 1. Ninety-eight approval. The survey link was distributed by the CFF percent (119/121) of respondents reported using anti- via email to the directors of all 261 CFF-programs on pseudomonal beta-lactam antibiotics during APE in June 4, 2010. The email included language assuring the their CF population. The most common answer for fre- confidentiality of survey participation, as well as quency of utilization of anti-pseudomonal beta-lactam instructions to forward the email to the most appropri- antibiotics was ‘‘FREQUENTLY’’ in both pediatric and ate respondent at their program if applicable. Reminder adult centers (see Table 1 for scale).
emails were sent out by the CFF on July 8, 2010 and Antibiotic utilization data for the study are reported August 2, 2010. The survey was closed on August 6, in Table 2. No significant regional differences were seen in both pediatric (P ¼ 0.23) and adult (P ¼ 0.5) The survey consisted of a maximum of 27 multiple respondents. Dosing regimens were defined based on choice and short answer questions depending on respondents’ answers. Skip logic was used to help dis-tinguish  Intermittent dose I (intermittent administration of (pediatric only, adult only, or both); the anti-pseudomo- antibiotics at doses lower than CFF and European nal beta-lactam utilized; and the dosing strategy employed (intermittent, extended infusion, or continu-  Intermittent dose II (intermittent administration of ous infusion). Each respondent was required to answer antibiotics at doses equal or greater than CFF and questions related to the respondents’ role in the center, and program demographic data (location, academic  Extended Infusion (antibiotic administered by affiliation, program size, and number of pediatric, and extended infusion or continuous infusion) adult patients). Respondents were also asked questions Ceftazidime was the most commonly utilized anti- regarding the anti-pseudomonal beta-lactam antibiotic pseudomonal beta-lactam by CFF-accredited care cen- utilized, frequency of utilization, and dosing regimen ters comprising 74/167 (44%) of all infusion regimens strategies. Respondents were given the opportunity to with 70/74 (95%) administered by an intermittent dose respond with ‘‘not applicable’’ or ‘‘other.’’ regimen. The majority of intermittent ceftazidimedoses, 56/70 (80%) administered were Intermittent dose I, with 150 mg/kg/day divided every 8 hr, dosed up to Frequencies and percentages were used to describe the 2 g every 8 hr; maximum 6 g/day) being the most com- program characteristics of the 121 respondents. For pur- mon [38/56 (68%)]. Similarly, dosing of other anti- poses of regional comparisons, the responses related to pseudomonal beta-lactams; aztreonam 1/2 (50%), cefe- anti-pseudomonal beta-lactam utilization were grouped pime 3/23 (13%), meropenem 9/20 (45%), piperacillin– into four geographic regions as defined by the U.S. Cen- tazobactam 18/32 (56%), and ticarcillin–clavulanate 3/8 sus Bureau: Northeast: CT, ME, MA, NH, RI, VT, NJ, (38%) were prescribed at doses lower than those recom- NY, PA; Midwest: IN, IL, MI, OH, WI, IA, NE, KS, ND, mended by the CFF and European guidelines (Table 2).
MN, SD, MO; South: DE, DC, FL, GA, MD, NC, SC, Twelve of the centers (7%) reported using extended VA, WV, AL, KY, MS, TN, AK, LA, OK, TX; West: infusion beta-lactam strategies in the survey. Only AZ, CO, ID, NM, MT, UT, NV, WY, AK, CA, HI, OR, one CFF-accredited care center reported consistently Survey of Anti-Pseudomonal Beta-Lactams in CF TABLE 1— Program Characteristics of Respondents documents.3–5 (Table 2) This is of particular concernbecause the CFF and European dosing recommen- dations are based on pharmacokinetic dosing studies which predict the need for higher antipseudomonal beta-lactam doses in CF patients.11–17 For example, the current CFF guidelines recommend a ceftazidime dos- ing strategy of 300 mg/kg/day divided every 6–8 hr.4 This recommendation is based on a theoretical dosing calculation study performed by Lietman.17 The dosing calculation was based on the following assumptions: first, the minimum inhibitory concentration of 90% of was 8 mm/ml; second, the trough concentration of ceftazidime needed to be 10 times higher than the MIC90 to ensure adequate penetration into bronchial secretions; third, the dosing interval of every 6 hr was based upon the ceftazidime half-life in CF patients of 1.5 hr; and lastly, the known volume of distribution of A limitation of the study is the survey response rate of 46% of all CFF-accredited care centers. Since more than half of the centers did not respond, the response Utilization of beta-lactams in all patients rate may limit the generalizability of the study results.
However, the response rate is comparable to the once- daily tobramycin utilization survey which had a 43% Frequency of beta-lactam utilization (pediatric) response rate, and the CFF-accredited care centers who responded represent 56% (14,856/26,740) of the CF patients in the CFF Patient Registry.2,18 In conclusion, this survey describes the previously unknown prevalence of utilization and dosing strategies Frequency of beta-lactam utilization (adult) of anti-pseudomonal beta-lactam antibiotics among CFF-accredited care centers in the United States. There was variability in drug choice and dosing strategies between centers. Intermittent infusions were reported to be the most frequently utilized anti-pseudomonal beta- lactam dosing strategy. However, it appears that most CFF-care centers are not utilizing the intermittent dos- ing strategies recommended by CFF and a European consensus statement guidelines.3–5 The clinical signifi-cance of this observation is unknown. The reasons forlower than recommended intermittent doses are alsounknown. Concern for adverse effects related to higher measuring beta-lactam levels as part of their monitoring antibiotic doses may be a reason, but studies have shown that CFF and European recommendations can beused safely.15,19,20 Lower than recommended intermit-tent dosing of anti-pseudomonal antibiotics, such as ceftazidime, could easily be optimized to meet the cur- To our knowledge, this study represents the first rent CFF and European dosing recommendations, but it attempt to quantify the utilization and dosing of anti- is not clear if this would result in a meaningful clinical pseudomonal beta-lactams in CFF-accredited centers.
benefit.3–5 Additional randomized, controlled studies The dosing strategies reported by the study respondents using clinical endpoints rather than microbiologic end- varied. Of note, over half (58%) of the respondents uti- points may be helpful in defining the optimal dosing lizing intermittent antipseudomonal beta-lactam dosing strategy for beta-lactam antibiotics in the treatment of regimens reported using dosing regimens lower than P. aeruginosa in pediatric and adult cystic fibrosis that recommended in CFF and European guidelines TABLE 2— Dosing Regimens for Each Anti-Pseudomonal Beta-Lactam 1Antibiotic administered at a dose lower than CFF and European recommendations.
2Antibiotic administered at a dose equal or greater than CFF and European recommendations.
10. U.S., Census Bureau 2000; Census 2000 Geographic Definitions [Online]. Available: http://www.census.gov/geo/www/us_regdiv.
The authors would like to thank the Intermountain pdf. html#US [Accessed on September 28, 2010].
Primary Children’s Medical Center Children’s Medical 11. Reed MD, Aronoff SC, Stern RC, Yamashita TS, Myers CM, Unit Pharmacy Team (Kellee Murdock, PharmD, Friedhoff LT, Blumer JL. Single-dose pharmacokinetics of Andrea Kemper, PharmD, Laurie Darnell, PharmD, aztreonam in children with cystic fibrosis. Pediatr Pulmonol1986;2:282–286.
Christina Ferdinand, PharmD, and Ekaterina Mattingly, 12. Huls CE, Prince RA, Seilheimer DK, Bosso JA. Pharmacoki- CPhT), and Alexander Elbert from the Cystic Fibrosis netics of cefepime in cystic fibrosis patients. Antimicrob Agents Foundation for their contributions to this project.
13. Reed MD, Stern RC, O’Brien CA, Yamashita TS, Myers CM, Blumer JL. Pharmacokinetics of imipenem and cilastatin inpatients with cystic fibrosis. Antimicrob Agents Chemother 1. Flume PA, Mogayzel PJ, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, Marshall BC. Clinical Practice Guidelines for 14. Bui KQ, Ambrose PG, Nicolau DP, Lapin CD, Nightingale CH, Pulmonary Therapies Committee. Cystic fibrosis pulmonary Quintiliani R. Pharmacokinetics of high-dose meropenem in guidelines: treatment of pulmonary exacerbations. Am J Resp adult cystic fibrosis patients. Chemotherapy 2001;47:153–156.
15. Reed MD, Stern RC, Myers CM, Klinger JD, Yamashita TS, 2. Van Meter DJ, Corriveau M, Ahern JW, Lahiri T. A survey of Blumer JL. Therapeutic evaluation of piperacillin for acute pul- once-daily dosage tobramycin therapy in patients with cystic monary exacerbations in cystic fibrosis. Pediatr Pulmonol fibrosis. Pediatr Pulmonol 2009;44:325–329.
3. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and man- 16. De Groot R, Hack BD, Weber A, Chaffin D, Ramsey B, Smith agement of pulmonary infections in cystic fibrosis. Am J Resp AL. Pharmacokinetics of ticarcillin in patients with cystic fibrosis: a controlled prospective study. Clin Pharmacol Ther 4. Microbiology and Infectious Disease in Cystic Fibrosis. Cystic Fibrosis Foundation Consensus Conference. 1994; Volume V, 17. Lietman PS. Pharmacokinetics of antimicrobial drugs in cystic fibrosis: b-lactam antibiotics. Chest 1988;84:115S–119S.
5. Doring G, Conway SP, Heijerman HGM, Hodson ME, Hoiby N, 18. Cystic Fibrosis Foundation Patient Registry 2009 Annual Data Smyth A, Touw DJ. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur 19. Hubert D, Le Roux E, Lavrut T, Wallaert B, Scheid P, Manach D, Grenet D, Sermet-Gaudelus I, Ramel S, Cracowski C, et al.
6. Nelson Textbook of Pediatrics 18th Edition by Kliegman, Behr- Continuous versus intermittent infusions of ceftazidime for man, Jenson, and Stanton; 2007, Elsevier, Inc. 1119, 1182.
exacerbations of cystic fibrosis. Antimicrob Agents Chemother 7. Red Book 29th Edition; 2009 Report of the Committee on Infectious Diseases; The American Academy of Pediatrics.
20. Zobell JT, Ampofo K, Cash J, Korgenski K, Chatfield BA. High 8. Drug Information Handbook. Lexi-Comp, Inc. 2010.
9. Pediatric Dosage Handbook. Lexi-Comp, Inc. 2010.
pediatric cystic fibrosis patients. J Cyst Fibros 2010;9:280–283.

Source: http://www.fundacionfibrosisquistica.org/guias_articulos/2011/A%20Survey%20of%20the%20Utilization%20of%20Anti-Pseudomonal%20betalactamicos%20en%20FQ-oct-2011.pdf