ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 2009, p. 5122–5126 Vol. 53, No. 12 0066-4804/09/$12.00 doi:10.1128/AAC.00064-09 Copyright © 2009, American Society for Microbiology. All Rights Reserved. Introduction of Ertapenem into a Hospital Formulary: Effect on Antimicrobial Usage and Improved In Vitro Susceptibility of Pseudomonas aeruginosaᰔ Ellie J. C. Goldstein,1,2* Diane M. Citron,1 Victoria Peraino,3 Tanya Elgourt,4 Anne R. Meibohm,5 and Shuang Lu5 RM Alden Research Laboratory, Santa Monica, California1; Departments of Infectious Diseases,2 Microbiology,3 and Pharmacy,4 St. Johns’ Health Center, Santa Monica, California 90404; and Merck & Co., Inc., North Wales, Pennsylvania5 Received 16 January 2009/Returned for modification 2 July 2009/Accepted 21 September 2009 After ertapenem was added to the formulary of a 344-bed community teaching hospital, we retrospectively studied its effect on antimicrobial utilization and on the in vitro susceptibility of various antimicrobial agents against Pseudomonas aeruginosa. Three study periods were defined as preintroduction (months 1 to 9), postin- Downloaded from troduction but before the autosubstitution of ertapenem for ampicillin-sulbactam (months 10 to 18), and after the policy of autosubstitution (months 19 to 48) was initiated. Ertapenem usage rose slowly from introduction to a range of 36 to 48 defined daily doses/1,000 patient days (DDD) with a resultant decrease in ampicillin- sulbactam usage due to autosubstitution. Imipenem usage peaked 6 months after the introduction of ertap- enem and started to decline coincidently with the increased use of ertapenem. During the second period, -Prior to the introduction of ertapenem, the suscepti .(0.002 ؍ ؊1.28; P؍ imipenem usage decreased (slope bility of P. aeruginosa to imipenem increased from 61 to 81% at month 7 but then decreased slightly to 67% at aac.asm.org month 9. After the introduction of ertapenem, susceptibility continued to increase; the increasing trend was P < 0.001). In the third period, the median susceptibility (interquartile range) was ;1.74 ؍ significant (slope 88% (82 to 95%). This change appeared related to decreased imipenem usage. For every unit decrease in the in the susceptibility of P. aeruginosa at IOWA STATE UNIV on January 23, 2010 (0.008 ؍ monthly DDD of imipenem, there was an increase of 0.38% (P to imipenem in the same month. Ertapenem was effective in our antimicrobial stewardship program and may have helped improve the P. aeruginosa antimicrobial susceptibility to imipenem by decreasing the unnecessary usage and selective pressure of antipseudomonal agents. The development of multidrug-resistant gram-negative stable ␤-lactams like ertapenem (15, 18). The FDA approved pathogens driven by antimicrobial selective pressures has be- ertapenem, a carbapenem (19) without Pseudomonas aerugi- come an increasing concern in hospitalized patients (1, 14, 16). nosa activity, for use against community-acquired pneumonia, For Enterobacteriaceae, ␤-lactamases such as the extended- complicated intraabdominal infections, pelvic infections, com- spectrum ␤-lactamases (ESBLs) and plasmid and chromo- plicated urinary tract infections, and skin and soft-tissue infec- somal AmpCs are probably the most important resistance tions, including diabetic foot infections. However, concern as mechanisms, although other extended-spectrum class A en- to whether ertapenem might adversely affect the activity of the zymes, such as KPC, also are emerging (1). For P. aeruginosa, carbapenems imipenem and meropenem against P. aeruginosa chromosomal AmpC, permeability changes (OprD), and the has been a barrier for its use. multidrug efflux pumps are probably the determining factors. Studies performed prior to ertapenem’s approval attempted Metallo-␤-lactamases are distinctly unusual in Enterobacteria- to define risk factors for Pseudomonas resistance (6, 11). Lau- ceae and P. aeruginosa in the United States but are a more tenbach et al. (11) found not only a higher mortality rate important problem in other geographic areas (10). The devel- (31.1%) for patients infected with an imipenem-resistant P. opment, spread, and persistence of these resistance mecha- aeruginosa than for those infected with imipenem-susceptible nisms complicates the selection of antimicrobial therapy when strains (16.7%) but also concluded that the only independent trying to avoid the increased selective pressures caused by the risk factor for imipenem resistance was fluoroquinolone use. utilization of any one class of antimicrobial agents. Conse- Fortaleza et al. (6) evaluated the problem of P. aeruginosa quently, the Infectious Diseases Society of America has issued resistance and concluded that imipenem, amikacin, and van- guidelines to enhance antimicrobial stewardship programs (4), comycin use were associated with imipenem-resistant P. aerugi- with goals that include minimizing the emergence of resistance nosa. Patterson (16) has reviewed the various conflicting stud- by the appropriate use of antimicrobials. ies of this topic and concludes that “the lack of alternative The increased importance of ESBL resistance in Escherichia agents on the horizon that are active against gram-negative coli and Klebsiella species has necessitated the use of ESBL- bacteria makes our efforts at controlling emergence of resis- tance all the more imperative.” Because we felt the addition of ertapenem to our formulary would have cost savings and clin- * Corresponding author. Mailing address: 2021 Santa Monica Blvd., ical utility but were concerned about collateral damage, we Suite 740 East, Santa Monica, CA 90404. Phone: (310) 315-1511. Fax: (310) 315-3662. E-mail: [email protected]. retrospectively studied the effect of the addition of ertapenem ᰔ Published ahead of print on 28 September 2009. on antimicrobial utilization and on the in vitro activity of imi- 5122 VOL. 53, 2009 INTRODUCTION OF ERTAPENEM INTO HOSPITAL FORMULARY 5123 TABLE 1. Usage of ertapenem and imipenem and susceptibility of P. aeruginosa to imipenem Susceptibility (%) of P. aeruginosa Ertapenem usage (DDD) Imipenem usage (DDD) to imipenem Period Months Percentilea Percentilea Percentilea Range Range Range 25 50 75 25 50 75 25 50 75 Prior to ertapenem usage 0–9 0 0 0 0 25 30 34 13–40 62 69 77 60–81 After addition of ertapenem 10–19 7 8 20 5–35 28 35 43 23–59 71 75 82 63–91 to formulary After policy substitution 20–48 39 44 53 24–79 22 25 29 13–50 82 88 95 67–100 a 50th percentile is the median; 25th and 75th percentiles are the first and third quartiles (interquartile range), respectively. penem, ertapenem, levofloxacin, cefepime, tobramycin, and RESULTS piperacillin-tazobactam on P. aeruginosa. (Parts of this study were presented previously at the 44th Table 1 and Fig. 1 show the monthly usage (DDD) of imi- Annual Meeting of the Infectious Diseases Society of America, penem and ertapenem and the susceptibility of P. aeruginosa to Downloaded from Toronto, Canada, 2006 [3].) imipenem during the 48 months of observation. The usage of ertapenem increased slowly from its introduction to the for- mulary in month 10 through month 15 (DDD ϭ 8), and then MATERIALS AND METHODS usage increased more sharply. Prior to the implementation of Study design. We retrospectively collected and analyzed data on the antimi- the policy of autosubstituting ertapenem for ampicillin-sulbac- crobial usage (defined daily dose/1,000 patient days [DDD]) and antimicrobial susceptibility for P. aeruginosa in a 344-bed community teaching hospital from tam, the DDD was 35. Subsequently through month 42, usage aac.asm.org January 2002 to December 2005. The hospital has a 51-bed oncology unit that is was relatively consistent, generally in the range of 36 to 48 DDD. involved in research programs, a 32-bed intensive care unit, and a 32-bed step- Toward the end of the observation period (months 43 to 48), down unit. The average daily census for the study period was approximately 200; ertapenem usage increased and then began to decrease again. the average length of stay varied from 4.6 to 9.1 days, with an average stay of 5 In the 9 months of observation prior to the introduction of days, excluding newborns and outliers. Ertapenem was added to the formulary in at IOWA STATE UNIV on January 23, 2010 September 2002, and in July 2003 a policy of autosubstituting ertapenem for ertapenem, the usage of imipenem increased significantly (13 ampicillin-sulbactam was instituted because of increased (40%) E. coli resistance to 39 DDD; slope ϭ 3.18; P Ͻ 0.001). Imipenem usage peaked to ampicillin-sulbactam and because of its relatively high cost. (Ampicillin-sul- in month 15 (DDD ϭ 59) and then started to decline (the slope ϳ bactam was $45/day, not including nursing and pharmacy time or the bag and during the second period was Ϫ1.28; P ϭ 0.002), which is intravenous administration setup materials for three to four daily administra- tions, while ertapenem was ϳ$45/day with one administration per day). The coincident in time with the sharper increase in the use of policy of reminding physicians to voluntarily substitute cefotaxime for cefepime ertapenem. Overall, usage declined significantly during the if no P. aeruginosa was isolated from cultures after 72 h of empirical therapy was second period (the change of slope was Ϫ4.46; P Ͻ 0.001). continued. No other antimicrobial-prescribing restrictions were instituted, and During the third period, imipenem usage was relatively con- no other new agents were added to the formulary during the study period. No unusual infection control measures were instituted during this period. stant, generally between 22 and 29 DDD. Contrary to the trend Statistical analysis. To investigate the trends in antibiotic usage in the sus- of increasing the use of imipenem prior to the introduction of ceptibility of P. aeruginosa, we first defined three periods in the 48-month study. ertapenem, there was a significant decrease in the use of imi- The first period, months 1 to 9, was prior to the introduction of ertapenem to the penem when ertapenem became available.