0066-4804/11/$12.00 doi:10.1128/AAC.00742-11
Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Reduction in Fluoroquinolone Use following Introduction of Ertapenem
into a Hospital Formulary Is Associated with Improvement
in Susceptibility of Pseudomonas aeruginosa to Group 2
Carbapenems: a 10-Year Study
䌤
Paul P. Cook,
1* Michael Gooch,
2and Shemra Rizzo
3Department of Medicine, Division of Infectious Diseases, Brody School of Medicine at East Carolina University, Greenville, North Carolina1; Department of Pharmacy, Pitt County Memorial Hospital, Greenville, North Carolina2; and
Department of Biostatistics, University of California at Los Angeles, Los Angeles, California3 Received 28 May 2011/Returned for modification 17 August 2011/Accepted 25 September 2011
We examined the effect of the addition of ertapenem to our hospital formulary on the resistance of nosocomial Pseudomonas aeruginosa to group 2 carbapenems (imipenem, meropenem, and doripenem). This was a retrospective, observational study conducted between 1 January 2000 and 31 January 2009 at a large, tertiary-care hospital. Autoregressive integrated moving average (ARIMA) regression models were used to evaluate the effect of ertapenem use on the susceptibility of Pseudomonas aeruginosa to group 2 carbapenems as well as on the use of the group 2 carbapenems, ciprofloxacin, and other antipseudomonal drugs (i.e., tobramycin, cefepime, and piperacillin-tazobactam). Resistance was expressed as a percentage of total isolates as well as the number of carbapenem-resistant bacterial isolates per 10,000 patient days. Pearson correlation was used to assess the relationship between antibiotic use and carbapenem resistance. Following the addition of ertapenem to the formulary, there was a statistically significant decrease in the percentage of Pseudomonas aeruginosa isolates resistant to the group 2 carbapenems (Pⴝ 0.003). Group 2 carbapenem use and the number of carbapenem-resistant Pseudomonas aeruginosa isolates per 10,000 patient days did not change significantly over the time period. There was a large decrease in the use of ciprofloxacin (Pⴝ 0.0033), and there was a correlation of ciprofloxacin use with the percentage of isolates resistant to the group 2 carbapenems ( ⴝ 0.47, Pⴝ 0.002). We suspect that the improvement in susceptibility of Pseudomonas aeruginosa to group 2 carba-penems was related to a decrease in ciprofloxacin use.
Ertapenem is a group 1 carbapenem with good activity against extended-spectrum -lactamase (ESBL)-producing
Enterobacteriaceae (13). Its activity against Pseudomonas aeruginosa is minimal, and there has been concern that overuse
of this agent may select isolates of P. aeruginosa that are re-sistant to the group 2 carbapenems (imipenem, meropenem, and doripenem). In vitro experiments have demonstrated that ertapenem is associated with a minimal risk of resistance de-velopment (14).
Previous reports have described no change in or improved susceptibility of Pseudomonas aeruginosa to carbapenems fol-lowing programs of replacing group 2 carbapenems with erta-penem in the hospital setting (6, 7, 11). We examined the effect of the addition of ertapenem to our hospital formulary on the susceptibilities of nosocomial isolates of Enterobacteriaceae,
Pseudomonas aeruginosa, and Acinetobacter baumannii to
group 2 carbapenems.
MATERIALS AND METHODS
Pitt County Memorial Hospital is an 861-bed, tertiary-care teaching hospital affiliated with the Brody School of Medicine at East Carolina University. The hospital has a trauma unit, cardiac medical unit, cardiothoracic surgery service,
orthopedic unit, pediatric unit, oncology service, and dialysis unit. Renal plantations are performed at the hospital, but there are no bone marrow trans-plantation or burn units. This was an observational study from 1 January 2000 until 31 December 2009. Our antibiotic stewardship program (ASP) was estab-lished in 2001 and has been described previously (1). Antimicrobial drug use was measured in defined daily doses per 1,000 patient days (DDD/1,000 PD), using the standards of the World Health Organization (www.whocc.no/atcddd/).
In vitro bacterial susceptibilities to imipenem and meropenem were
deter-mined with a MicroScan system (Dade Behring). Gram-negative bacilli were tested for susceptibility to imipenem between 2000 and 2006 and for suscepti-bility to meropenem between 2006 and 2009. Beginning in 2008, meropenem-resistant isolates were tested for susceptibility to doripenem by the Etest method
(bioMe´rieux). The nosocomial Gram-negative data sets were created by querying
CareFusion, Medmined, Inc. (Birmingham, AL). All clinical specimens (blood, sterile fluid, sputum, urine, wound, and anaerobic specimens) positive for
Pseu-domonas aeruginosa between 1 January 2000 and 31 December 2009 at Pitt
County Memorial Hospital were included in the database. Surveillance cultures were excluded. In an effort to limit the analysis to nosocomial cases, we included only cultures obtained from patients in the hospital more than 2 days following admission for evaluation. Duplicate positive test results from the same patient within a 3-month period were counted only once. Resistance was defined as the percentage of the total isolates that were resistant to the selected antimicrobial agents. Intermediately susceptible isolates were counted as resistant. Rates of nosocomial, carbapenem-resistant, Gram-negative cases were expressed as the numbers of bacterial isolates per 10,000 patient hospital days.
Statistical analysis was performed using PROC ARIMA in SAS, version 9.2. Autoregressive integrated moving average (ARIMA) regression models were used as a means to evaluate the effect of ertapenem use on the susceptibility of
Pseudomonas aeruginosa to group 2 carbapenems and the usage of the group 2
carbapenems, ciprofloxacin, and other antipseudomonal drugs (i.e., tobramycin, cefepime, and piperacillin-tazobactam). The ARIMA model describes a univar-iate time series as a function of its past values and other significant exogenous variables like ertapenem use and long-term linear trends. The time trend was a
* Corresponding author. Mailing address: Department of Medicine, Brody School of Medicine at East Carolina University, 6A Doctors Park, Greenville, NC 27834. Phone: (252) 5700. Fax: (252) 744-3472. E-mail: [email protected].
䌤Published ahead of print on 3 October 2011.
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count variable numbered from 1 to 40 according to the time series measured in quarters. In each model, appropriate parameters of the ARIMA model were found to account for the autocorrelation of the time series.
Ertapenem was added to the hospital formulary in April 2002. Since the introduction of ertapenem was gradual, lag effects were considered in the model. Lag effects of ertapenem use were not found significant in the models for the susceptibility of Pseudomonas aeruginosa to group 2 carbapenem or for group 2 carbapenem and ciprofloxacin use and were not included in the models. In these cases, previous values for ertapenem use were not significant in describing the present value of the outcomes. However, in the models for other antipseudo-monal drugs, denominator factors were included. A significant denominator factor for ertapenem use describes its effect as an infinite distributed lag model with exponentially declining weights. In other words, previous values of erta-penem use affect the present outcome and said effect decreases exponentially the further it is back in time. To adjust for multiple hypothesis testing, we used Dunnett’s correction (4). For a joint significance level of 0.05, each hypothesis was tested at a significance level of 0.0084. Pearson’s correlation coefficient was used to determine the association of antimicrobial use with the percentages and rates of carbapenem-resistant Pseudomonas aeruginosa.
RESULTS
Antimicrobial drug use. Following introduction of erta-penem to the hospital formulary, there was a gradual increase in the use of the drug (Fig. 1). The use of the group 2 carba-penems (imipenem, meropenem, and doripenem) did not change significantly over the 10-year period (P ⫽ 0.8439) (Table 1; Fig. 1). The use of ciprofloxacin decreased dramat-ically during this same time period (P⫽ 0.0033) (Table 1; Fig. 1). The use of other antipseudomonal drugs was variable fol-lowing the addition of ertapenem. Cefepime and
piperacillin-tazobactam use increased (P⫽ 0.0007 and P ⫽ 0.005, respec-tively) and tobramycin use decreased (P⬍ 0.0001). The use of antipseudomonal drugs as a group (i.e., tobramycin, cefepime, ciprofloxacin, piperacillin-tazobactam, and group 2 carbapen-ems) decreased (P⬍ 0.0001) following the addition of erta-penem to the formulary (Table 1) (Fig. 2).
Susceptibility of Pseudomonas aeruginosa to group 2 carba-penems.There were 3,002 nonduplicate, nosocomial isolates of
Pseudomonas aeruginosa over the 10-year period. There was an
FIG. 1. Ertapenem, group 2 carbapenem (imipenem, meropenem, and doripenem), and ciprofloxacin use in defined daily doses per 1,000 patient days (DDD/1000 PD) and percentage of Pseudomonas aeruginosa isolates resistant to the group 2 carbapenems over the 10-year time period. Ciprofloxacin use and percent carbapenem-resistant P. aeruginosa isolates were plotted using a 5-quarter moving-average transformation. Time increments are in quarters. Ertapenem was added to the hospital formulary in April 2002.
TABLE 1. Correlation of ertapanem use with percent carbapenem-resistant Pseudomonas aeruginosa isolates and use of
antipseudomonal drugsa
Variable Correlation P value
DDD ciprofloxacin/1,000 PD ⫺0.91786 0.0033b DDD group 2 carbapenem/1,000 PD 0.62346 0.8439
% CRPA isolates ⫺0.45815 0.003b
No. of CRPA isolates/10,000 PD ⫺0.38245 0.867 DDD tobramycin/1,000 PD ⫺0.53182 ⬍0.0001b
DDD cefepime/1,000 PD 0.75647 0.0007b
DDD piperacillin-tazobactam/1,000 PD 0.41702 0.005b DDD antipseudomonal drugs/1,000 PD ⫺0.52802 ⬍0.0001b
a
Correlation of each of the variables with ertapenem use along with the P values for ertapenem use in the ARIMA model. DDD, defined daily dose; 1,000 PD, 1,000 patient days; CRPA, carbapenem-resistant Pseudomonas aeruginosa; antipseudomonal drugs, group 2 carbapenems, ciprofloxacin, cefepime, pipera-cillin-tazobactam, and tobramycin.
b
Significant at the 0.0084 level under Dunnett’s correction.
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average of 58⫾ 14 isolates per quarter in period 1 (quarters 1 to 10), and an average of 81⫾ 12 isolates per quarter in period 2 (quarters 11 to 40). There was a significant decrease in the percentage of Pseudomonas aeruginosa isolates resistant to the group 2 carbapenems (imipenem, meropenem, doripenem) following the introduction of ertapenem (Fig. 1) (P⫽ 0.003). The rate of group 2 carbapenem-resistant Pseudomonas
aerugi-nosa isolates (number of carbapenem-resistant isolates per
10,000 patient days) did not change significantly (P⫽ 0.867). There was a correlation of ciprofloxacin use with both the percentage of carbapenem-resistant Pseudomonas aeruginosa isolates ( ⫽ 0.47; P ⫽ 0.0020) (Fig. 3) and the rate of carba-penem-resistant Pseudomonas aeruginosa isolates ( ⫽ 0.36;
P⫽ 0.024).
Susceptibility of Enterobacteriaceae and Acinetobacter bau-mannii isolates to group 2 carbapenems.The effect of increas-ing carbapenem use on other Gram-negative bacilli was exam-ined. Over the 10-year time period, there were no significant changes in the susceptibilities of nosocomial
Enterobacteria-ceae or Acinetobacter baumannii isolates to the group 2
car-bapenems. Greater than 99% of the nosocomial
Enterobac-teriaceae isolates were susceptible to the group 2 carbapenems
throughout the 10-year time period.
Number of isolates of Stenotrophomonas maltophilia, Acineto-bacter baumannii, and Klebsiella pneumoniae carbapenemase-producing organisms.There was no change in the number of nosocomial Stenotrophomonas maltophilia isolates per 10,000 patient days, whereas the number of nosocomial Acinetobacter
baumannii isolates per 10,000 patient days decreased following
the addition of ertapenem to the formulary (P⫽ 0.01). We did not observe any Klebsiella pneumoniae carbapenemase-produc-ing organisms durcarbapenemase-produc-ing the 10-year period.
FIG. 2. Use of antipseudomonal drugs over the 10-year study period. Usage is defined in daily doses per 1,000 patient days (DDD/1000 PD). Data were plotted using a 5-quarter moving-average transformation.
FIG. 3. The percentage of carbapenem-resistant Pseudomonas
aeruginosa isolates plotted versus the use of ciprofloxacin in defined
daily doses per 1,000 patient days. There was a correlation of cipro-floxacin use with the percentage of carbapenem-resistant Pseudomonas
aeruginosa isolates ( ⫽ 0.47; P ⫽ 0.0020).
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DISCUSSION
Previous reports have described improved susceptibility of
Pseudomonas aeruginosa to group 2 carbapenems following
implementation of programs that substituted ertapenem for the group 2 carbapenems (6, 7, 11). In these programs, the authors concluded that the improved susceptibilities were re-lated to decreased group 2 carbapenem use. Our data demon-strate an improved susceptibility of Pseudomonas aeruginosa to imipenem despite no significant change in the use of the group 2 carbapenems. This paradox appears to be explained by the dramatic decrease in ciprofloxacin use that occurred following the introduction of ertapenem. Most clinical carbapenem re-sistance in Pseudomonas aeruginosa is related to loss of or decrease in the levels of the outer membrane porin protein OprD with or without overexpression of the MexAB-OprM efflux system (8, 12, 15, 16). Quinolone use leads to upregula-tion of the Mex efflux pumps, including the MexEF-OprN efflux pump. Induction of this particular pump is associated with reduced levels of OprD, the porin system essential for carbapenem entry into the cell and subsequent activity (8). Meropenem and doripenem, but not imipenem, are substrates for the MexEF-OprN efflux pump (8). Therefore, quinolone use may lead to cross-resistance to all of the group 2 carba-penems, either by increased efflux (meropenem and dori-penem) or by decreased porin entry (imipenem, meropenem, and doripenem). Previous clinical studies support this concept. Lautenbach et al. (10) showed in a case-controlled study that prior fluoroquinolone use was the only independent risk factor for acquisition of imipenem-resistant Pseudomonas aeruginosa. Our hospital used a large quantity of ciprofloxacin prior to the addition of ertapenem to the formulary. Because of in-creasing resistance of Pseudomonas aeruginosa to ciprofloxacin at our institution, we implemented a program to decrease its use (2).The program initially consisted of pharmacy
recom-mendations of alternative therapies but subsequently involved restriction of its use (i.e., requiring approval from the infec-tious diseases service) beginning July 2007. There was a signif-icant decrease in the use of antipseudomonal drugs following the introduction of ertapenem. This decrease was driven, in large part, by the steep drop in ciprofloxacin use. We postulate that it was this drop in ciprofloxacin use that led to the im-provements in susceptibilities of the group 2 carbapenems.
There was a discrepancy with regard to the percentage and the rate of group 2 carbapenem resistance. We have previously reported the lack of correlation between these two metrics in reporting antimicrobial resistance (2). We suspect that one of the reasons was the increase in the number of Pseudomonas
aeruginosa isolates after the introduction of ertapenem.
Be-tween 2000 and 2009, there was an increase in the number of intensive-care-unit beds in the hospital. As a result, there was a disproportionate increase in the number of patients at high risk for developing infections with Pseudomonas aeruginosa. Therefore, it is not surprising that we did not see a change in the rate of carbapenem-resistant Pseudomonas aeruginosa fol-lowing the introduction of ertapenem. In fact, one might have expected to see an increase in the rate of carbapenem-resistant
Pseudomonas aeruginosa had there been no decrease in the
percentage of isolates resistant to the carbapenems.
Our hospital had imipenem and meropenem on the
formu-lary from 2000 to 2006. Imipenem was dropped from the for-mulary in 2006, and doripenem replaced meropenem in 2008. One might expect that there would have been an improvement in the susceptibilities with the switch from imipenem to mero-penem and then to dorimero-penem because of the reported lower MIC of doripenem against Pseudomonas aeruginosa. In this study, however, the imipenem-resistant isolates of
Pseudomo-nas aeruginosa were either resistant or intermediately
suscep-tible to meropenem in greater than 75% of those tested (data not shown). Also, more than 75% of the meropenem-resistant isolates were resistant or intermediately susceptible to dori-penem (data not shown). In this and many other studies, in-termediately susceptible isolates were classified as resistant. Therefore, although there may be slight differences in the MICs of doripenem, meropenem, and imipenem with regard to Pseudomonas aeruginosa, the differences were not enough to affect the results of this study.
Overuse of any antimicrobial agent is usually associated with the development of resistance. There is concern that overuse of carbapenems may lead to an increase in infections with
Stenotrophomonas maltophilia (17) or Klebsiella pneumoniae
carbapenemase-producing organisms (9). We did not see an increase in nosocomial Stenotrophomonas maltophilia isolates following introduction of ertapenem to the formulary. Further-more, we did not see any cases of nosocomial carbapenemase-producing Klebsiella pneumoniae. Other investigators have sug-gested that use of fluoroquinolones may be risk factors for acquisition of both Stenotrophomonas maltophilia (3) and car-bapenemase-producing Klebsiella pneumoniae (5, 9, 15, 18).
There are several limitations of this study. First, given that the study utilized aggregate microbiology data, it is difficult to distinguish colonization from infection. Many of the isolates were from tracheal aspirates or from patients with urinary catheters, and there was no chart review to try to distinguish colonization from infection. Second, rates of nosocomial infec-tion are affected by infecinfec-tion control practices. Our hospital instituted a policy of screening all incoming patients for nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) in February 2007. All patients who screened positive were placed in private rooms with strict contact isolation in-fection control measures. It is possible that because of the placement of more high-risk patients on contact precautions, there was a decrease in the spread of several multidrug-resis-tant organisms, including Pseudomonas aeruginosa,
Acineto-bacter baumannii, and Stenotrophomonas maltophilia.
In summary, the addition of ertapenem to our hospital for-mulary had no effect on the susceptibilities of
Enterobacteria-ceae and Acinetobacter baumannii and was associated with an
improvement in the susceptibility of Pseudomonas aeruginosa to group 2 carbapenems. We suspect that the explanation for the latter phenomenon may be related to the decrease in the use of ciprofloxacin. Fluoroquinolones are inducers of efflux pumps, particularly MexEF-OprN, which is associated with a decrease in the number of OprD porin channels (8). Since efflux pumps are associated with resistance to a variety of antimicrobial agents, including -lactams, aminoglycosides, and quinolones, substituting ertapenem for a fluoroquinolone may be a means of reducing both carbapenem-resistant and multidrug-resistant Pseudomonas aeruginosa.
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ACKNOWLEDGMENTS
The study was supported in part by a grant from Merck & Co., Inc. Paul Cook is a member of the Speakers’ Bureau of Merck and Astellas. He has received research support from Merck, Gilead, and Pfizer.
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