Reduction in broad-spectrum antimicrobial use associated with no improvement in hospital antibiogram

Paul P. Cook1,*, Paul G. Catrou2, John D. Christie1,2, Pamela D. Young3,§ and Ronald E. Polk4

1 Division of Infectious Diseases, Department of Medicine, Brody School of Medicine at East Carolina University, Brody 3E-113, Greenville, NC 27858; 2 Department of Pathology, Brody School of Medicine at East Carolina University, Greenville, NC 27858; 3 University Health Systems of Eastern Carolina, Greenville, NC; 4 Departments of Pharmacy and Medicine, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA, USA

Received 6 November 2003; returned 13 January 2004; revised 29 January 2004; accepted 3 February 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective: To evaluate the effect of an antimicrobial management programme on broad-spectrum antimicrobial use and antimicrobial susceptibilities of common nosocomial pathogens at a tertiary-care teaching hospital.

Methods: Review of hospital charts of patients who had been prescribed broad-spectrum antimicrobials 48 h earlier. Recommendations to streamline or discontinue antimicrobials were made based on results of available microbiology data, radiography studies, as well as the working diagnosis at the time of review. The charts were reviewed again on the following day to assess acceptance or rejection of the recommendations. Antimicrobial use, measured as defined daily dose per 1000 patient days (DDD/1000 PD), was determined before and after the antimicrobial management programme was started and was assessed as the mean quarterly use in the six quarters preceding implementation of the programme compared to the most recent six quarters that the programme has been in existence. Antibiotic susceptibilities were obtained from the clinical microbiology laboratory.

Results: Compared to the six quarters before the programme, broad-spectrum antibiotic use decreased by 28% (693 DDD/1000 PD to 502 DDD/1000 PD, P = 0.003). Total antifungal agent use decreased by a similar amount, i.e. 28% (144 DDD/1000 PD to 103 DDD/1000 PD, P = 0.02). Total antimicrobial use decreased by 27% (1461 DDD/1000 PD to 1069 DDD/1000 PD, P = 0.0007). Susceptibilities of common nosocomial Gram-negative organisms to commonly prescribed antibiotics did not change significantly over the 3 years of the programme. The rate of methicillin-resistant Staphylococcus aureus increased significantly in the non-intensive care areas of the hospital (P = 0.02) and decreased significantly in the intensive care areas of the hospital (P = 0.009) over the 4 year period from 2000 to 2003.

Conclusion: Implementation of an antibiotic management programme resulted in substantial reductions in both broad-spectrum and total antimicrobial consumption without having a significant impact on antibiotic susceptibilities of common Gram-negative microorganisms within the institution. The changes in MRSA rate in the non-ICU and ICU settings may reflect infection control measures that were in place during the study period.

Keywords: antimicrobial utilization, resistance, cost containment, prescribing interventions


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The emergence of antimicrobial resistance is a global problem that has been felt both in the community setting as well as within hospitals. Overuse of antimicrobials in both of these settings has contributed to the problem. It has been suggested that 20–50% of antibiotic usage in the community is inappropriate, e.g. for viral upper respiratory infections.1 Use of antimicrobials within the hospital setting is no better, with 50% of use determined to be unnecessary.2 Hospitals, because of the high concentration of very sick patients, are especially vulnerable to the development of antimicrobial resistance. Other factors that contribute to the problem within hospitals include the use of invasive devices, antimicrobial prophylaxis for procedures, and the increase in the number of immunosuppressed patients.3

Several methods have been advocated to improve antimicrobial use within hospitals. These include: passive prescriber education; standardized antimicrobial order forms; formulary restrictions; and computerized physician order entry.2,4 Prescriber education and order forms have not been proven to be effective. Formulary restrictions, particularly with regard to ceftazidime, have been effective in reducing the incidence of extended-spectrum ß-lactamase producing organisms within individual hospitals and intensive care units.5 However, formulary restrictions, when offset by increased use of another unrestricted broad-spectrum drug, can have a negative impact on resistance, the so-called ‘squeezing the balloon’ effect.6

Because of increasing antimicrobial resistance within our hospital, we implemented an antimicrobial management programme, beginning in January 2001. The purpose of the programme was to reduce use of broad-spectrum antibiotics by monitoring the use of these agents, and providing recommendations for streamlining or discontinuing antibiotics once culture data and diagnostic studies were available for review. We compared antimicrobial use in the six quarters before instituting the programme to use in the most recent six quarters in which the programme has been in place. Despite reducing total antimicrobial use by 28%, there was no significant change in antimicrobial susceptibilities of common Gram-negative pathogens in the first 3 years of the programme.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Pitt County Memorial Hospital is a 731-bed tertiary-care teaching hospital. The medical staff consists of faculty members of the Brody School of Medicine of East Carolina University as well as private physicians in the community. Physician orders are written by house officers as well as by private physicians.

The Antimicrobial Management Programme began in January 2001. The programme was formulated by the Antibiotic Utilization Stewardship Subcommittee and approved by the Pharmacy and Therapeutics Committee of the hospital and subsequently by the Medical Executive Committee of the medical staff before implementation. The key personnel of the programme included a clinical pharmacist as well as an infectious diseases physician. The programme affected the adult medical and surgical services, but not the paediatric service. All antimicrobials were classified as unrestricted, controlled or restricted (Table 1). Restricted antimicrobials required prior approval by the Infectious Diseases staff before the drugs could be dispensed by the pharmacy. The pharmacist reviewed a computer-generated report of all patients receiving controlled drugs and reviewed patient charts 2 days after the initial order for appropriate use of the controlled and restricted drugs Monday through Thursday. Based on microbiology culture results, radiology reports and the working diagnosis, the pharmacist, with input from the infectious diseases practitioner, made recommendations to change or stop the controlled antimicrobial agents. The recommendations were placed in the order section of the patient’s chart, immediately in front of the most recent order. For example, a patient admitted to the hospital with a diagnosis of pneumonia is treated with ceftriaxone and azithromycin. At day 3 of the patient’s hospitalization, cultures of the blood are positive for Streptococcus pneumoniae, which is susceptible to penicillin. If the patient were clinically stable and taking oral medications without difficulty, the pharmacist would suggest discontinuation of azithromycin and ceftriaxone, and starting penicillin or amoxicillin orally. If the patient was not taking oral medications or was clinically unstable, the pharmacist would recommend therapy with intravenous penicillin in place of ceftriaxone and azithromycin. The attending physician or housestaff would have 24 h to either accept or reject the recommendation. If, at the end of the 24 h time period, there was no response to the recommendation, the pharmacist would then write the recommended changes as orders. The recommendations were retrospectively reviewed to determine acceptance rates. Complete acceptance was defined as either passive or active acceptance of the entire recommendation of the pharmacist. Partial acceptance was defined as an acceptance of some, but not all, of the recommendation.


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Table 1. Categorization of ‘restricted’ and ‘controlled’ drugs
 
Pitt County Memorial Hospital participates in the SCOPE-MMIT Antimicrobial Surveillance Network. MMIT (MediMedia Information Technologies, Yardley, PA, USA) electronically extracts all inpatient antibiotic dispensing data from billing records at participating hospitals based upon recognition of antibiotic codes using the Uniform System of Classification (IMS, Plymouth Meeting, PA, USA) for antibacterial drugs (code 15000), antiviral drugs (code 82000) and antifungal drugs (code 38000). The total grams of individual antibiotics dispensed to inpatients for all routes of administration are used along with total patient days (PD) for the period of interest (quarterly and annually) to calculate the defined daily dose/1000 PD (DDD/1000 PD). The DDD figures represent the 2003 revisions of the World Health Organization (WHO) (www.whocc.no/atcddd/). This measure of antibiotic use is recommended by the WHO as the most appropriate metric to compare antibiotic use between institutions as well as between countries, and has been used by the Centers for Disease Control and Prevention’s Project ICARE to examine the relationships between antibiotic use and resistance in the intensive care unit.7,8 Quarterly antimicrobial use data were available for review from 1999 through 2003.

Bacterial susceptibilities were determined with MicroScan (Dade Behring, Inc., West Sacramento, CA, USA). Susceptibility results were compiled from the laboratory information system files. Duplicate isolates from the same patient were counted only once. Intermediate susceptibility was counted as susceptible. The percentage of susceptible isolates for common bacterial pathogens was determined for each time period. In addition, organism susceptibility was tallied by patient location at time of culture.

Statistical analysis

Proportions were analysed by {chi}2 test with use of P < 0.05 as the level of significance for susceptibility studies. Quarterly antimicrobial use and monthly antimicrobial purchase data were compared by a paired two-tailed t-test with P < 0.05 as the level of significance. Since antimicrobial use data were available for only six quarters (i.e. 18 months) before starting the antimicrobial management programme, the statistical analysis compared the antibiotic use data for the most recent six quarters of the programme to these pre-programme quarters.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Partial or complete acceptance of the recommendations occurred in 92% of cases (Table 2). The average quarterly broad-spectrum antibiotic use decreased by 28% (693 DDD/1000 PD to 502 DDD/1000 PD, P = 0.003) (Table 3). There were statistically significant reductions in the use of amikacin, ampicillin–sulbactam, aztreonam, cefotaxime, ceftriaxone, imipenem–cilastatin and piperacillin–tazobactam (Table 3). There was a trend toward decreased use of ciprofloxacin (P = 0.059). The decrease in ciprofloxacin use was not a result of a switch to another quinolone as use of the quinolone class as a whole decreased (Figure 1). Total antibiotic consumption, which included all intravenous and oral antibiotics dispensed from the pharmacy, decreased by 27% from 1461 DDD/1000 PD to 1069 DDD/1000 PD (P = 0.0007).


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Table 2. Number of charts for which a change in antimicrobial agent was recommended in the first 3 years of the programme as well as a breakdown of the number of partial and complete acceptances of the recommendations
 

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Table 3. Antibacterial use by specific drug between 1999 and 2003
 


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Figure 1. Use of broad-spectrum antimicrobials by class over a 5 year period. Broad-spectrum ß-lactams include third- and fourth-generation cephalosporins, carbapenems and monobactams. There has been a steady decrease in broad-spectrum antibiotic use since the programme began in 2001.

 
Use of other drugs not considered broad-spectrum antibiotics also decreased. Metronidazole use decreased by 54% (29.5 DDD/1000 PD to 13.6 DDD/1000 PD, P = 0.0003). There was no significant change in the use of vancomycin, clindamycin or tobramycin. There was a trend toward less fluconazole use (P = 0.10). Although there was a slight increase in other antifungal drugs, total antifungal agent use decreased by 28% (144 DDD/1000 PD to 103 DDD/1000 PD, P = 0.02). See Table 4.


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Table 4. Antifungal drug use
 
Susceptibilities of common Gram-negative organisms to several broad-spectrum antimicrobial agents are shown in Table 5. There were no significant changes in the susceptibilities of the organisms over the 4 year period. There was a significant increase in methicillin-resistant Staphylococcus aureus (MRSA) rate in the non-ICU setting (P = 0.02), whereas the rate of MRSA in the ICU setting actually decreased over the 4 year period (P = 0.009) (Table 6).


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Table 5. Percentages of common Gram-negative organisms susceptible to several antibiotics between 2000 and 2003
 

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Table 6. Rate of oxacillin/methicillin-resistant S. aureus in the ICU and non-ICU settings
 
The financial effects of this programme were analysed. First, total costs of antimicrobials were determined over a 5 year period. As can be seen in Figure 2, antimicrobial costs decreased in the first year of the programme and have continued to decrease slightly since that time. There was a 20% decrease in monthly antimicrobial costs ($340 591 in 2000 to $274 030 in 2003, P = 0.024). The percentage of the hospital pharmacy budget that includes antimicrobial agents decreased from 23.8% in 2000 to 15.3% in 2003 (P < 0.0001). There were no significant changes in individual drug acquisition costs to account for the difference in antimicrobial costs or percentage of the hospital pharmacy budget.



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Figure 2. Antimicrobial costs and percentage of pharmacy costs over a 5 year period. The antimicrobial management programme began in January 2001.

 
Length of stay was essentially unchanged (1999, 5.7 days; 2000, 5.8 days; 2001, 5.8 days; 2002, 5.7 days; 2003, 5.8 days). Mortality rates were also not significantly altered since the programme began (1999, 5.65/100 discharges; 2000, 3.96/100 discharges; 2001, 3.97/100 discharges; 2002, 3.72/100 discharges; 2003, 3.98/100 discharges).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our data demonstrate the effectiveness of an antimicrobial management programme in reducing the use of broad-spectrum antibiotics. The study is important in that it shows that there was a reduction in total antibiotic use rather than use of a specific drug. Previous studies have shown that a restrictive policy targeting a single drug, e.g. ceftazidime, was effective in reducing the incidence of extended spectrum ß-lactamase producing bacteria.5 Restriction of specific drugs has the disadvantage of promoting the overuse of other drugs on the formulary, the so-called ‘squeezing the balloon’ effect.6 White et al.9 demonstrated an improvement in antibiotic susceptibility through all units in a hospital after imposing restrictions on several broad-spectrum agents. Again, the reduction in the restricted agents was associated with an increase in unrestricted agents such as ceftriaxone, cefotetan and tobramycin. Our programme differs in that it involves restriction of only a few drugs and monitoring of several broad-spectrum agents. Recommendations for changing from broad-spectrum to narrow-spectrum antibiotics or recommendations for discontinuation of antibiotics were made once culture and susceptibility data were available from the microbiology laboratory. This programme actually resulted in a reduction in total antibiotic use. Rather than squeezing the balloon by restricting use of certain antibiotics, the programme has been able to reduce the use of broad-spectrum intravenous and oral antibiotics without resulting in a compensatory increase in other antimicrobials.

Acceptance of the programme was high with over 90% of the recommendations being at least partially accepted and 80% of the recommendations being accepted as written. We suspect that the acceptance of the programme related to the fact that culture and susceptibility data were available at the time of the recommendations. This additional data justified a change to less broad-spectrum agents. In contrast to other streamlining programmes, the recommendations became an order after 24 h unless the attending physician or housestaff actually rejected the recommendation in writing along with a reason for the rejection. The number of infectious diseases consultations did not change significantly once the programme was initiated (data not shown). In fact, in some cases, the recommendation to stop or change an antibiotic actually prompted a formal infectious diseases consultation. Therefore, even though the programme was voluntary, inaction on the part of the attending physician or housestaff resulted in an ‘acceptance’ of the recommendations and may explain the success of the programme.

There was very little change in susceptibilities of common Gram-negative bacteria to the broad-spectrum antimicrobials. The rate of MRSA in areas of the hospital outside of the intensive care units actually increased after the programme was implemented, whereas the MRSA rate in the intensive care units decreased. We suspect that there are many reasons to explain our findings. First, there is a clear association of antibiotic use with antibiotic resistance but much less data to support the concept that reducing antibiotic use actually leads to improvements in antibiotic susceptibilities.1013 Antibiotics provide enormous selection pressure for the development of antibiotic-resistant bacteria. Removal of the selection pressure does not guarantee that the antibiotic resistance genes will be lost by the resident microflora. Second, increasing recognition of community-acquired MRSA14,15 may partially explain the increase in our rate of MRSA from the non-ICU patients (which included the Emergency Department and ambulatory care units of the hospital). Moreover, there is substantial evidence linking the use of antimicrobials as growth promoters in the agriculture industry to the development of antibiotic resistance in the community.1620 Our programme obviously does not address the issue of antibiotic use and resistance in the community. Finally, with regard to the decreased rate of MRSA in the intensive care units of the hospital, this most likely reflects infection control measures that were instituted during the time period of the study.

In summary, acquisition of antibiotic-resistant organisms within the hospital is multifactorial such that infection control practices, severity of illness and community use of antibiotics all contribute to the problem.16,21,22

As a result, any single intervention is not likely to have a major effect on the rate of antibiotic resistance, especially in a short period of time. Perhaps a more realistic goal of an antibiotic management programme is to prevent the continued growth of antimicrobial resistance. Despite the fact that we did not demonstrate any appreciable improvement in antibiotic susceptibilities, we also did not observe any worsening in antibiotic resistance at our institution. In order to demonstrate an improvement in antimicrobial susceptibilities, it is likely that total antimicrobial use both in the hospital and in the community will need to decrease substantially.

The programme was initiated to combat the emerging problem of antibiotic resistance. However, reduction in use of broad-spectrum antibiotics will also reduce pharmacy costs. This programme has been quite successful in that regard. The cost savings in the first 3 years of the programme were over two million dollars. These savings more than justify the salary of a full time pharmacist and partial salary of an infectious diseases clinician to oversee the programme.

In summary, our data support the use of an antibiotic management programme as an effective means of controlling excessive antimicrobial use in the hospital setting. Although we did not see an improvement in antibiotic susceptibilities at our institution, we, likewise, saw no further deterioration in our hospital antibiogram. We contend that there are many factors that contribute to the problem of increasing antibiotic resistance. As such, interventions that focus only on the hospital setting are unlikely to have a tremendous immediate impact. Judicious use of antimicrobial agents is essential to the long-term efficacy of these drugs. Controlling antibiotic use in the hospital setting is feasible. A much more daunting task is the control of these drugs in the community setting and in the agricultural industry.


    Acknowledgements
 
We would like to thank Dr Cassandra Salgado for assistance with the statistical analysis of the data. No external financial support was obtained by any of the authors for the preparation of this manuscript.


    Footnotes
 
* Corresponding author. Tel: +1-252-744-2550; Fax: +1-252-744-3472; E-mail: cookp{at}mail.ecu.edu Back

§ Present address. Department of Pharmacy, University of Louisville Health Care, Louisville, KY, USA Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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