Non-Restrictive Antimicrobial Stewardship Program in a General and Emergency Surgery Unit

Abstract

Background:

The goal of an antimicrobial stewardship program (ASP) is to prevent the emergence of antimicrobial drug resistance and reduce adverse drug events, optimizing the selection, dosing, and duration of therapy in individual patients.

Methods:

This retrospective study evaluated changes in antimicrobial agent use associated with implementation of an ASP in a general and emergency unit. The pre-intervention and post-intervention periods were defined as July 1, 2013, to December 31, 2013 (pre-intervention) and January 1, 2014, to June 30, 2014 (post-intervention).

Results:

The mean total monthly antimicrobial use decreased by 18.8%, from 1,074.9 defined daily doses (DDD) per 1,000 patient-days to 873.0 DDD per 1,000 patient-days after the intervention. There was a significant reduction in the use of piperacillin-tazobactam, by 33.7% (p < 0.05), in imipenem/cilastatin, by 63.9% (p < 0.05), in meropenem by 68.0% (p < 0.05), and in levofloxacin by 45.0% (p < 0.05) without any negative effect on patient susceptibility to infections. Indeed, patient outcomes, including deaths, length of stay in the hospital, and re-admission within 30 days were not affected.

Conclusions:

The implementation of an education-based ASP achieved a significant improvement in all antimicrobial agent prescriptions in the surgical unit and a reduction in antimicrobial drug consumption, even when no restrictive measures were implemented.

Surgeons prescribing antibiotics have two contradictory responsibilities. On the one hand, they should offer optimal therapy for the individual patient under their care; on the other hand, they should preserve the efficacy of antibiotics and minimize the rate of emergence of drug-resistant strains and collateral damage of antibiotics (such as Clostridium difficile infections) [1]. In the past few decades, an increasing prevalence of infections caused by antibiotic-resistant pathogens, including extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella spp., Enterococcus species, carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, and Klebsiella pneumoniae carbapenemase producers, has been observed in surgical departments.

With few new antibiotics emerging, particularly for the gram negative spectrum or organisms, prudent antibiotic use is the only option to delay the emergence of resistance. In particular, both ESBL-producing Enterobacteriaceae [2] and carbapenem-resistant Enterobacteriaceae (CRE) [3] represent a serious public health threat in many countries. In this context, antibiotic stewardship programs (ASPs) play a crucial role in encouraging appropriate antibiotic use [4]. This is important, as antimicrobial drug therapy or prophylaxis has been reported to be inappropriate in >50% of hospitalized patients [5 –8].

The goal of an ASP is to prevent the emergence of antimicrobial resistance and reduce adverse drug events, including secondary infections (e.g., Clostridium difficile infection), by optimizing the selection, dosing, and duration of antimicrobial agent therapy in individual patients [9]. Several studies comparing antimicrobial drug use before and after introduction of an ASP have shown a reduction in drug consumption and related costs by reducing inappropriate prescribing practices and length of hospital stays [10 –13]. Formulary restriction and pre-authorization strategies are core aspects of ASPs [14,15]. However, in hospitals with limited resources, the best means of improving antimicrobial stewardship probably involves the collaboration of various specialties, not only the prescribing clinicians. This study evaluated changes in antimicrobial drug use associated with implementation of a non-restrictive ASP in a general and emergency surgical unit.

Patients and Methods

Study design

This study evaluated changes in antimicrobial drug use associated with implementation of an ASP based on two guidelines: Hospital guidelines for pre-operative antimicrobial prophylaxis and the World Society of Emergency Surgery (WSES) guidelines for the management of intra-abdominal infections, updated in 2013 [16]. We hypothesized that implementation of this ASP would lead to a reduction in the use of antimicrobial agents, particularly of carbapenems, and therefore, we compared the six-month period before ASP implementation to the six-month period after ASP using primary and secondary outcome measures.

Study setting and population

The study was conducted in the General and Emergency Surgery Unit at Macerata Hospital, Italy. Macerata Hospital serves as a secondary care unit for an area with a population of 324,000 inhabitants, and it has approximately 420 beds. In this hospital, the multi-disciplinary infection control committee meets monthly. Its active members are an infectious diseases specialist, a hospital pharmacist, a microbiologist, an intensivist, a pulmonary disease specialist, an infection control practitioner, an administrator, and a surgeon. The committee periodically reviews the local patterns of drug resistance in the medical institution. The General and Emergency Surgery Unit is a secondary care unit performing mainly elective major abdominal and emergency surgery. Antimicrobial use and other outcomes were collected for all surgical patients admitted to this unit during the study period. The study used anonymous, aggregate, and retrospective data.

Intervention

During 2013, hospital guidelines for antimicrobial prophylaxis were developed by a task force including a surgeon, a hospital pharmacist, and an infectious diseases specialist. Specific recommendations for doses, re-dosing intervals, and preferred agents for selected surgical procedures were included in the guidelines. In 2013, WSES guidelines for the management of intra-abdominal infections were published [16]. The General and Emergency Surgery Unit of Macerata Hospital participated in their implementation. The empirically designed antimicrobial drug regimen for management of intra-abdominal infections was based on the patient's clinical condition, the pathogens presumed to be involved, and the risk factors indicative of major resistance patterns. On January 1, 2014, these guidelines, accepted by the infection control committee, were introduced in this surgical unit and were accessible to all physicians. A one-day training curriculum was developed focusing on the principles of antibiotic use for prophylaxis and therapy [17]. Attendance was mandatory for all surgeons. Both guidelines were illustrated, and skills to apply them in the clinical setting were developed.

Copies of both guidelines were distributed to all surgeons. Posters were produced and displayed in the ward. All surgeons prescribed antibiotics without any restriction; however, consumption of some antimicrobial agents including carbapenems, tigecycline, and echinocandins were monitored by the hospital pharmacy. Antimicrobial prophylaxis prescribed by surgeons was checked in the operating room by the anesthesiologist at the time of administration. Initial antimicrobial therapy for patients with intra-abdominal infections was empirical because critically ill patients need immediate treatment even though microbiologic data (culture and susceptibility results) may require up to 24–72 h to determine a targeted therapy. A prospective audit of antimicrobial agent use with intervention and feedback to the prescriber were granted by an internal surgeon with expertise in antimicrobial management of surgical infections. The pre-intervention and post-intervention periods were defined as July 1, 2013, to December 31, 2013 (pre-intervention) and January 1, 2014, to June 30, 2014 (post-intervention).

Outcomes

The primary outcome was total systemic (oral or parenteral) antimicrobial drug use, measured in defined daily doses (DDD) per 1,000 patient-days per month. The Anatomical Therapeutic Chemical/DDD Index 2016 of the World Health Organization (WHO) Center for Drugs Statistics Methodology was used in the calculation of DDDs [18]. Antimicrobial data were acquired from the database of the Pharmacy Department as total grams dispensed to the Department of Surgery. Patient-days were obtained from the hospital's administrative database. Secondary outcome measures were the use of specified antibiotic agents or classes; antimicrobial agent costs; antimicrobial sensitivity of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae; Clostridium difficile infection; incidence of infection; and clinical outcomes, which included monthly mortality rates and lengths of stay. Antimicrobial costs were calculated as euros per patient-day per month and were obtained from the pharmacy database.

The sensitivity rates (%) of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae isolates to antibiotics from clinical samples were assessed. These organisms were selected a priori because they were the three most commonly isolated gram negative organisms in our intervention. Only the first isolate per patient per hospital stay was included unless there was a change in antimicrobial susceptibility. In this case, subsequent isolates with additional antimicrobial drug resistance were included. Specimens were accepted from all clinical sites cultured with two exceptions. Respiratory specimens from patients with cystic fibrosis were excluded, because these patients often are chronically colonized with multi-drug-resistant organisms that, in most instances, reflect antimicrobial use prior to arrival in the ward. Additionally, screening swabs collected for infection control purposes were not included. Susceptibility data were obtained from the clinical microbiology laboratory information system. Minimum inhibitory concentration (MIC) breakpoints were defined in compliance with the Clinical Laboratory Standards Institute documents. Incidence rates of Clostridium difficile infections (number of cases per 1,000 patient-days) were calculated from the clinical microbiology laboratory information system and the hospital's administrative database. Clinical outcomes, including mortality rates, lengths of stay, and re-admissions within 30 days; and age, gender, and admitting diagnosis were available from the hospital's administrative database

Statistical analysis

The differences in median values before and after introduction of the ASP in the gender, admitting diagnosis, mortality rate, and re-admission rate within 30 days were assessed by the χ² method. The differences in median values before and after ASP in the age, length of stay, amount of antimicrobial agents used, antimicrobial therapy costs, and incidence rates of Clostridium difficile infections were assessed by the nonparametric Mann–Whitney U test. The differences before and after ASP in the sensitivity rates of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae isolates to antibiotics were assessed by χ² test or Fisher exact test. It was regarded as statistically significant when the p value was <0.05. Two-tailed tests were conducted for all the assessments. EpiInfo 5.3.1 for Windows was used for all the statistical calculations.

Results

During the pre-intervention period, 651 patients were admitted to the surgical unit, corresponding to 4,531 patient-days. In the post-intervention period, there were 618 patients admitted, making up 4,403 patient-days. There were no significant differences in age, sex, admitting diagnosis, mortality rate, length of stay, or re-admission between the two intervention periods (Table 1).

Table 1.

Comparison of Clinical Outcomes, Mortality Rate, Length of Stay (d), and Re-Admission within 30 Days in the Pre- and Post-Intervention Period

Variable	Pre-Intervention	Post-Intervention	p
Admissions	651	618
Mean age ± standard deviation (SD)	62.6 ± 20.0	61.0 ± 20.1	0.14^a
Male (%)	297 (45.6)	288 (46.6)	0.77
Admitting diagnosis (%)			0.61
Urgent surgery	350 (53.8)	342 (55.3)
Planned surgery	301 (46.2)	276 (44.7)
Percent died	1.5	1.9	0.74
Mean length of stay (d) (± SD)	7.0 ± 8.1	7.1 ± 8.5	0.10^a
Re-admission within 30 d (%)	43 (6.6)	30 (4.9)	0.22

All p values were calculated using χ² test unless otherwise noted.

Mann-Whitney U test.

The mean total monthly antimicrobial agent use decreased by 18.8%, from 1,074.9 DDD per 1,000 patient-days to 873.0 DDD per 1,000 patient-days after the intervention (Table 2). With respect to specific agents and classes of antimicrobial drugs, there was a significant reduction in piperacillin-tazobactam use, by 33.7% (p < 0.05), in imipenem/cilastatin, by 63.9% (p < 0.05), in meropenem, by 68.0% (p < 0.05), and in levofloxacin, by 45.0% (p < 0.05). The mean total cost of antimicrobial drugs decreased from 8.5 euros per patient-day (standard deviation 3.9 euros per patient-day) before the intervention to 5.9 euros per patient-day (standard deviation 3.8 euros per patient-day) after the intervention (p = 0.34), with an overall cost savings of 34% seen in the post-intervention period.

Table 2.

Comparison of Use of Specific Antimicrobial Drug Classes and Agents Measured in Defined Daily Doses per 1,000 Patient-Days in the Pre- and Post-Intervention Periods

Class or Agent	Mean Pre-Intervention (SD)	Mean Post-Intervention (SD)	p
Antibacterials	1074.9 (212.4)	873.0 (411.2)	0.26
Antifungals	21.2 (20.6)	48.5 (45.2)	0.30
Ampicillin-sulbactam	171.9 (123.5)	95.5 (77.8)	0.42
Amoxicillin-clavulanic acid	191.0 (38.4)	186.6 (95.7)	0.87
Piperacillin-tazobactam	153.8 (24.0)	101.9 (39.4)	<0.05
Cefazolin	100.2 (27.9)	163.4 (61.2)	0.05
Ceftriaxone	36.2 (51.0)	14.5 (12.5)	0.75
Ceftazidime	0	5.5 (5.1)	<0.05
Imipenem-cilastatin	33.2 (14.9)	12.0 (13.8)	<0.05
Meropenem	30.3 (16.0)	9.7 (10.7)	<0.05
Ertapenem	0	7.2 (12.2)	0.14
Ciprofloxacin	171.5 (57.4)	131.5 (77.2)	0.20
Levofloxacin	118.9 (27.0)	65.4 (48.3)	<0.05
Gentamicin	18.4 (10.1)	19.9 (15.2)	1.00
Tigecycline	22.2 (17.4)	16.6 (25.7)	0.26
Vancomycin	0	0	NA
Metronidazole	27.4 (17.6)	43.3 (35.2)	0.23

All p values calculated using Mann–Whitney U test.

Abbreviations: NA = not applicable; SD = standard deviation.

There were no statistically significant differences in the antimicrobial susceptibility of E. coli, P. aeruginosa, or K. pneumoniae isolates between the pre- and post-intervention periods (Table 3). The rate of C. difficile infection did not differ, being stable at 0.21 cases per 1,000 patient-days both pre-intervention and post-intervention (p = 0.90). The reduction in antibiotic use was not accompanied by significant negative effects on patient outcomes, including mortality rate, length of stay, or re-admission within 30 days.

Table 3.

Susceptibility of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae Isolates to Commonly Used Antibiotics ^a

	Pre-Intervention	Post-Intervention	p
E. coli
Ampicillin	6/15 (40.0)	9/27 (33.3)	0.92
Cefotaxime	12/14 (85.7)	18/27 (66.7)	0.35
Ciprofloxacin	6/15 (40.0)	16/27 (59.3)	0.38
TMP-SMX	9/15 (60.0)	18/27 (66.7)	0.92
Piperacillin-tazobactam	13/14 (92.9)	23/27 (85.2)	0.83
Imipenem	9/10 (90.0)	20/20 (100)	0.71
Gentamicin	14/15 (93.3)	23/27 (85.2)	0.77
Tobramycin	13/15 (86.7)	21/27 (77.8)	0.77
P. aeruginosa
Ceftazidime	5/8 (62.5)	7/9 (77.8)	0.44^b
Ciprofloxacin	6/8 (75.0)	8/9 (88.9)	0.45^b
Piperacillin-tazobactam	5/8 (62.5)	8/9 (88.9)	0.24^b
Imipenem	4/7 (57.1)	6/8 (75.0)	0.43^b
Gentamicin	7/8 (87.5)	8/9 (88.9)	0.74^b
Tobramycin	7/8 (87.5)	7/9 (77.8)	0.55^b
K. pneumoniae
Ciprofloxacin	4/15 (26.7)	4/6 (66.7)	0.11^b
Levofloxacin	4/13 (30.8)	4/5 (80.0)	0.09^b
Cefotaxime	5/15 (33.3)	5/6 (83.3)	0.05^b
Ceftazidime	4/15 (26.7)	5/6 (83.3)	0.05^b
Imipenem	6/13 (46.2)	4/5 (80.0)	0.23^b
Meropenem	6/15 (40.0)	5/6 (83.3)	0.09^b
Gentamicin	12/15 (80.0)	4/6 (66.7)	0.45^b

Number of isolates susceptible/total number of isolates tested (%). All p values were calculated using χ² test unless otherwise noted.

Calculated using Fisher exact test.

TMP-SMX = trimethoprim-sulfamethoxazole.

Discussion

In this study, we demonstrated that implementation of an ASP based on both local guidelines for pre-operative antimicrobial prophylaxis and WSES guidelines for the management of intra-abdominal infections yielded an immediate and clinically significant drop in antimicrobial drug use. We observed an overall reduction of drug use of 18.8%, and this reduction was seen mainly for antibiotics as imipenem-cilastatin and meropenem, which should be used only in critically ill patients with intra-abdominal infections because they may promote antimicrobial drug resistance among Enterobacteriaceae.

These results complement those reported in a recent systematic review of stewardship interventions in critical care units, where reductions in antimicrobial drug use of 11%–38% were observed [19]. Other studies have focused their intervention and outcome on “targeted antimicrobials” [20], but this approach is associated with a compensatory increase in the prescription of unrestricted antibiotics [21]. The results from our study demonstrated a reduction in overall antimicrobial drug use.

The most important result of our trial is the significant reduction in the use of imipenem-cilastatin and meropenem, which dropped from 33.2 to 12.0 DDD per 1,000 patient-days (p < 0.05) and from 30.3 to 9.7 DDD per 1,000 patient-days (p < 0.05), respectively. This is important because carbapenem-resistant Enterobacteriaceae (CRE) are emerging rapidly worldwide, and epidemiologic studies have shown a link between carbapenem use and resistance [22]. Carbapenems have been used widely in many countries because of the increasing rate of ESBL-producing Enterobacteriaceae causing an increase in resistance to these antibiotics [23]. Carbapenems with coverage of Pseudomonas aeruginosa, including imipenem, meropenem, and doripenem, should be curtailed in community-acquired infections, where highly resistant species are not typical and therefore usually do not require a broad-spectrum regimen [24]. One exception is the alarming rise in the frequency of ESBL genetic elements. Risk factors for infection by ESBL-carrying organisms include recent receipt of broad-spectrum antibiotics (especially fluoroquinolones), prior infection or colonization with ESBL-expressing organisms, recurrent infections, and chronic indwelling catheters, as well as a stay in long-term care facilities, where ESBL-expressing organisms are endemic [25]. The recent rapid spread of carbapenem-resistant Klebsiella pneumoniae [26 –28] should be a serious challenge for clinicians, and reduced carbapenems use should be mandatory in every hospital setting.

Another important finding was the reduction in fluoroquinolone use, both ciprofloxacin and levofloxacin. In particular, the reduction in levofloxacin use was statistically significant, dropping from 118.9 to 65.4 DDD per 1,000 patient-days (p < 0.05). Fluoroquinolones have been used widely in the last two decades for the management of intra-abdominal infections, because of their excellent activity against aerobic gram negative bacteria, oral availability, and tissue penetration [29]. However, resistance of Enterobacteriaceae to fluoroquinolones has increased over this time [30]. Therefore, the use of ciprofloxacin as first-line treatment for severe infections can no longer be recommended in many regions of the world. The reduction of its use is important, because these antibiotics have been associated with a low threshold for emergence of resistance, including ESBLs, as well as a greater risk of Clostridium difficile infection [31,32].

The antimicrobial therapy costs decreased from 8.5 euros per patient-day before the intervention to 5.9 euros per patient-day after the intervention (p = 0.3), with an overall cost savings of 34% in the post-intervention period. Other studies conducted in community hospitals reported a reduction of antimicrobial therapy costs of 13.3%–25.8% per patient-day [33 –35].

The lack of change in resistance patterns was not unexpected. Although stewardship interventions have been associated with protection against the emergence of resistance, a longer followup period may be required to appreciate changes in local ecology [36]. For example, a reduction in nosocomial infections caused by antibiotic-resistant organisms was not observed until three years after implementation of a previous intervention [37]. The reduction in antibiotic use was not accompanied by significant negative effects on patient outcome, including mortality rate, length of stay, or re-admission within 30 days.

There were some limitations to this study. First, the data were retrospective. In addition, the ideal primary outcome would be the appropriateness of antimicrobial therapy, rather than antimicrobial use. However, standardized definitions of appropriate and inappropriate therapy are still lacking [38], and evaluating appropriateness is subjective. The literature has highlighted that antimicrobial agents often are overused, and a reduction in their use is a rational goal [38] for an ASP. Furthermore, the measurement of antibiotic use by DDDs per 1,000 patient-days may be discordant for many frequently used antibacterial drugs, because the administered dose differs from the DDD recommended by the World Health Organization [39].

Because physicians are primarily responsible for the decision to use antibiotics, educating them about the attitudes and knowledge that underlie their prescribing behavior is crucial for improving antimicrobial prescription. Education is an essential element of any program designed to influence prescribing behavior. It may provide knowledge, attitude, and perception to prescribers about antimicrobial drug management. In this study, the implementation of an education-based ASP achieved a significant improvement in all antimicrobial prescriptions in the surgical unit and a reduction in antimicrobial consumption, even when no restrictive measures were implemented.

Conclusions

In hospitals with limited resources, the best means of improving antimicrobial stewardship is the collaboration of various specialties, including surgeons. The implementation of an education-based ASP achieved a significant improvement in all antimicrobial prescriptions in the center and a reduction in antimicrobial consumption even though no restrictive measures were implemented. In this era of multidrug-resistant micro-organisms, every community hospital worldwide should have a multidisciplinary hospital infection control committee, including infectious disease specialists, hospital pharmacists, microbiologists, infection control practitioners, administrators, and prescribing clinicians. Among the surgical team, surgeon understanding of the necessary principles of microbiology, infectious diseases, and clinical pharmacology is crucial to encourage the application of prudent prescribing. Having local opinion leaders collaborate on the development of institutional guidelines may improve compliance by promoting ownership of the guidance.

Footnotes

Author Disclosure Statement

The authors have no conflicts of interest to report.

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