Research Research Prescribing trends before and after implementation of an antimicrobial stewardship program

Kelly A Cairns p to 50% of antimicrobial BPharm, Abstract GradDipClinPharm, agents prescribed to hospital Objectives: Antimicrobial stewardship programs are recommended to reduce Antimicrobial Stewardship 1 inpatients are considered to be Pharmacist U by reducing inappropriate use of antimicrobials. We inappropriate,1,2 and this excess use implemented an antimicrobial stewardship program and aimed to evaluate its Adam W J Jenney effect on broad-spectrum antimicrobial use. MB BS, FRACP, FRCPA, has been associated with increased Infectious Diseases mortality, adverse drug reactions and Design, setting and participants: Observational study with historical control and using interrupted time series analysis conducted in a tertiary referral hospital. Microbiologist1,2 the development of resistant bacte- ria.3,4 The Australian Commission on Hospital inpatients prescribed restricted antimicrobials for non-standard Iain J Abbott indications, where approval had expired or without approval. MB BS, Safety and Quality in Health Care 1 Intervention: Baseline period of 30 months immediately followed by an Microbiology Registrar recently published recommendations 18-month intervention period commencing January 2011. Matthew J Skinner for hospital-based antimicrobial stew- Main outcome measures: Number and type of interventions made by MB BS, FRACP, ardship programs.2 A variety of General Physician1,3 antimicrobial stewardship team; monthly rate of use of broad-spectrum approaches are available to imple- antimicrobial agents (in defined daily doses/1000 occupied bed-days). Joseph S Doyle ment these recommendations, MB BS, MSc, FRACP, Results: The antimicrobial stewardship team made 1104 recommendations in Infectious Diseases including dissemination of guidelines, 779 patients during the 18-month intervention period. In 64% of cases, the 1 Physician education, restricting antimicrobial recommendation was made to cease or de-escalate the antimicrobial , Michael Dooley availability and postprescribing audit or to change from intravenous to oral therapy. The introduction of the BPharm, and review. intervention resulted in an immediate 17% (95% CI, 13%–20%) reduction in Director of ,1 and broad-spectrum antimicrobial use in the intensive care unit and a 10% (95% CI, Professor of Clinical We aimed to evaluate changes in Pharmacy, Centre for 4%–16%) reduction in broad-spectrum antimicrobial use outside the intensive Medication Use and Safety2 antimicrobial prescribing after the care unit. Reductions were particularly seen in cephalosporin and glycopeptide implementation of an antimicrobial use, although these were partially offset by increases in the use of -lactam–- Allen C Cheng lactamase inhibitors. MPH, PhD, FRACP, stewardship program in a specialist Deputy Head, Infection tertiary referral hospital. Conclusions: The introduction of an antimicrobial stewardship program, Prevention and Hospital including postprescription review, resulted in an immediate reduction in broad- Epidemiology Unit,1 and Associate Professor of spectrum antimicrobial use in a tertiary referral centre. However, the effect of Infectious Diseases Methods this intervention reduced over time. Epidemiology2

Setting 1 Alfred Health, full-time pharmacist was appointed in macist and either an ID registrar and/ Melbourne, VIC. Alfred Health is a health service com- January 2011. Before this, authorisa- or an ID physician, on weekdays) com- 2 Monash University, prising three hospitals in metropolitan tion to prescribe restricted antimicro- menced in January 2011. Each round Melbourne, VIC. 3 Sir Charles Melbourne. The largest campus, the bial agents required approval from comprised a focused review of clinical Gairdner Hospital, Alfred Hospital, is a 430-bed tertiary infectious diseases (ID) registrars, but notes and results of investigations Perth, WA. teaching hospital with , sur- auditing had suggested poor compli- aimed at establishing the indication, allen.cheng@ gery and trauma services. It includes ance. In the new system, online planned duration, appropriateness, monash.edu immunocompromised populations approval could be obtained to use and alternatives to the use of restricted (including patients with HIV, cystic restricted antimicrobials for pre- antimicrobial agents. Recommenda- MJA 2013; 198: 262–266 fibrosis and heart/lung transplantation, approved indications that were tions were discussed with the treating doi: 10.5694/mja12.11683 and haematology and bone marrow included in national or local consen- team and documented in writing; the transplantation) and is supported by a sus guidelines. Short-term approval final decision regarding patient man- 35-bed intensive care unit (ICU). was granted for other indications agement was the responsibility of the The Medical Journal of Australia ISSN: 0025- specified by the clinician (non-stand- treating team. Patients who required 729X 18 March 2013 198 5 262-266 Antimicrobial stewardship program ard indications). Pharmacists could more in-depth management advice ©The Medical Journal of Australia 2013 www.mja.com.auWe have previously described the pre- alert the antimicrobial stewardship were referred to the ID consult service. Research liminary activities of the antimicrobial team of unauthorised antimicrobial Patients were reviewed by the stewardship team.5 A web-based use exceeding 24 hours (pharmacist stewardship team if they were antimicrobial approval system (Guid- alerts). receiving at least one restricted anti- ance MS, Melbourne Health) was Non-ICU antimicrobial stewardship microbial for a non-standard indica- rolled out from October 20106 and a ward rounds (by the stewardship phar- tion, where approval had expired, or

262 MJA 198 (5) · 18 March 2013 Research

1 Existing infectious diseases services and antimicrobial stewardship interventions augmented this from January 2011 introduced during the study with all patients reviewed routinely. In December 2010, there was also a Existing infectious diseases services change to empirical ICU guidelines Antimicrobial stewardship interventions introduced during this study for health care-acquired sepsis, from Intensive care Heart/lung transplantation ticarcillin/clavulanate or cefepime Surgical specialties Haematology/bone (for early and late sepsis, respec- Rehabilitation General medicine marrow transplantation tively) to piperacillin/tazobactam Acute geriatric care Other medical specialties Cystic fibrosis (regardless of onset), in all cases Community hospital Emergency department Burns combined with an aminoglycoside,

Increasing patient acuity except when combined with qui- nolone in specified situations. Rec- Existing ID ommendations for use support Telephone- Routine ID based support Formal ID consultation on request ward rounds did not change. service Outcome measures We compared trends in the rate of use Audit and Antimicrobial stewardship rounds feedback of antimicrobial classes before stew- ardship implementation (January

Antimicrobial Web-based antimicrobial approval 2008 to December 2010) and after restriction implementation (January 2011 to June 2012). Antimicrobial consumption quantities were converted into where a pharmacist alert had been received a formal ID consult, or were defined daily doses (DDD) per 1000 created. At our hospital, 13 restricted admitted under lung transplant/ occupied bed-days (OBD) as part of antimicrobial agents require web- cystic fibrosis, haematology and the National Antimicrobial Utilisation based approval: amikacin, azithro- bone marrow transplant, or burns Surveillance Program.7,8 Total broad- mycin, cefepime, ceftazidime, ceftri- services, where ID per- spectrum antimicrobial use was axone, , meropenem, formed regular ward rounds (Box 1). defined as the sum of usage for all moxifloxacin, piperacillin/tazo- For several years in the ICU, the classes except for aminoglycosides, bactam, teicoplanin, ticarcillin/cla- microbiology registrar has discussed which are regarded as narrow-spec- vulanate, tobramycin and results and antimicrobial treatments trum . Antimicrobial use is vancomycin. Patients were not with ICU teams daily (supported by based on pharmacy purchasing data reviewed by the antimicrobial stew- an ID physician three times per and inpatient stock distribution ardship team if they had already week). The stewardship pharmacist (excluding hospital in the home and

2 Change in antimicrobial use before and after implementation of antimicrobial stewardship interventions

Before intervention After intervention Change

Trend Trend Change Immediate change Change in trend Antimicrobial class/setting Use* (%/month)† Use* (%/month)† in use† (95% CI)‡ (95% CI)§ Intensive care

Total broad spectrum 1021.8 0 937.1 1.0%  8.3%  16.6% ( 19.9%,  13.2%) 1.0% (0.7%, 1.4%)

Aminoglycosides 137.0  2.0% 75.2  0.5%  45.1%  20.3% ( 30.2%,  9.1%) 1.5% (0.4%, 2.7%)

Antipseudomonal -lactam– 129.1 0.3% 191.3 0.6% 48.2% 34.2% (21.8%, 47.9%) 0.3% ( 0.5%, 1.1%) -lactamase inhibitor

Carbapenems 113.8 0.4% 133.9 2.4% 17.6%  11.2% ( 20.7%,  0.6%) 2.1% (1.2%, 3.0%)

Cephalosporins 219.2 0.8% 131.2 1.6%  40.2%  54.6% ( 59.0%,  49.7%) 0.8% ( 0.1%, 1.7%) (3rd/4th generation)

Fluoroquinolones 318.3  0.7% 278.4 0.1%  12.5%  3.3% ( 10.1%, 4.0%) 0.7% (0.1%, 1.4%)

Glycopeptides 241.4  0.2% 202.3 1.5%  16.2%  24.8% ( 31.1%,  18.0%) 1.7% (1.0%, 2.5%) General wards (excluding intensive care)

Total broad spectrum 357.8 0.1% 333.4 0.3%  6.8%  9.9% ( 15.7%,  3.7%) 0.2% ( 0.4%, 0.8%)

Aminoglycosides 63.7  1.0% 55.8  0.7%  12.5% 9.8% ( 6.7%, 29.1%) 0.3% ( 1.1%, 1.7%)

Antipseudomonal -lactam– 50.5  0.4% 54.5 1.9% 8.1%  2.9% ( 18.5%, 15.7%) 2.3% (0.9%, 3.7%) -lactamase inhibitor

Carbapenems 52.9  0.4% 53.5 0.1% 1.0% 6.7% ( 10.0%, 26.5%) 0.5% ( 0.9%, 2.0%)

Cephalosporins 90.1 0.5% 80.3 0.7%  10.9%  22.4% ( 32.3%,  11.1%) 0.2% ( 1.0%, 1.4%) (3rd/4th generation)

Fluoroquinolones 81.8 0 74.0  0.6%  9.6%  4.2% ( 16.7%, 10.3%)  0.6% ( 1.8%, 0.7%)

Glycopeptides 82.5 0.3% 71.2  0.4%  13.8%  14.2% ( 25.6%,  1.2%)  0.7% ( 2.0%, 0.5%)

* Defined daily doses per 1000 occupied bed-days. † Positive represents increased use; negative, decreased use. ‡ Change in use at the time of the introduction of the intervention. § Relative change in monthly rate of use. ◆

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the emergency department). Out- 3 Antimicrobial use before and after implementation of the antimicrobial stewardship ward rounds, by comes were assessed by: class of antimicrobial agent • the mean rate of antimicrobial use ICU Non-ICU in the intervention period 1400 450 compared with the pre-interven- Total broad spectrum tion period; 1200 400 • model-predicted immediate change in antimicrobial use 1000 350 between the end of the pre- 800 300 intervention period and the OBD DDD/1000 commencement of the interven- tion period (immediate change); 600 250 300 100 • model-predicted change in the rate Aminoglycosides of antimicrobial use between the pre-intervention period and post- 200 80 intervention period (change in

trend); 100 60 • the immediate change and the OBD DDD/1000 change in trend in antimicrobial 40 use were both assessed using 0 80 segmented Poisson regression. Antipseudomonal 250 β-lactam− We defined a clinically significant β-lactamase 70 200 decrease in antimicrobial use as: inhibitor 60 • a statistically significant (P < 0.05) 150 immediate decrease in the rate of 50 100 antimicrobial use; and/or OBD DDD/1000 40 • a statistically significant decrease in 50 30 the rate of change of antimicrobial 300 80 use in the intervention period Carbapenems compared with the pre-interven- 70 tion period. 200 60 Statistical tests were performed 50 using Stata version 12 (StataCorp). 100

Ethical permission to review these OBD DDD/1000 40 data was obtained from the Alfred 0 30 Health Human Ethics Committee. Cephalosporins 350 140 (3rd/4th generation) 300 120 Results 250 100 200 Impact of antimicrobial 80 stewardship rounds OBD DDD/1000 150 Between 10 January 2011 and 30 June 100 60 2012, 2254 patients were identified as Fluoroquinolones 500 120 requiring review by the antimicrobial stewardship team. An antimicrobial 400 100 management recommendation was made in 779 of 2254 (35%) patients, 300 80 with a total of 1104 recommendations 200 60 made. Of the patients for whom a OBD DDD/1000 recommendation was made, the 100 40 350 100 median age was 66 years (range, 16– Glycopeptides 98 years) and 503 (65%) were male. 300 Recommendations were made in 80 patients under 26 different treating 250 units; 63% (490/779) of patients were 200 60 managed by surgical/trauma units DDD/1000 OBD DDD/1000 150 and 37% (289/779) were medical 100 40 patients. The median duration of anti- 0 8 2008 y 2012 00 2009 2011 microbial therapy before review was 2 ly l ly uly 2010 uly Ju July 2009 July 201 July 2011 Ju July 2 Ju J J July 2012 days (interquartile range, 1–4 days). Month and year Month and year The majority of recommendations DDD/1000 OBD = defined daily doses per 1000 occupied bed-days. ICU = intensive care unit. Solid vertical line represents commencement of intervention. Dotted lines represent pre-intervention and post-intervention trends in antimicrobial use. ◆ were made following pharmacy alerts

264 MJA 198 (5) · 18 March 2013 Research

(907/1104; 82%), by non-standard intervention, the rate of broad-spec- confounders such as concurrent approvals (92/1104; 8%) or based on trum antimicrobial use increased by changes in ICU empirical treatment expiry of the current antimicrobial 0.1% per month; following the inter- guidelines. Aggregated data on anti- approval (93/1104; 8%). vention, it increased by 0.3% per microbial use is not able to provide a Recommendations were made to month (P = 0.49). Changes in the use measure of appropriateness of use modify treatment for patients on of specific classes of antimicrobials are and does not account for changes in restricted broad-spectrum antimicrobi- detailed in Box 2 and Box 3. antimicrobial dosing. The data on als; most commonly, ceftriaxone (278), antimicrobial use includes units piperacillin/tazobactam (155), cipro- known to be high users of broad- floxacin (99) and vancomycin (96). Discussion spectrum antimicrobials (eg, cystic In 40% (440/1104) of recommen- fibrosis) but where the only new dations, antimicrobial discontinua- The antimicrobial stewardship pro- intervention was the introduction of tion was suggested; in an additional gram brought immediate reductions in the web-based approval system. A 11% (123/1104), antimicrobial de- the use of total broad-spectrum anti- formal cost-effectiveness study was escalation was recommended; and in microbials, particularly third/fourth not undertaken; however, we note 13% (145/1104), an intravenous to generation cephalosporins and glyco- that the antimicrobial classes where oral switch was recommended. Esca- peptides. In addition to case-by-case significant decreases in use were seen lation of antimicrobial spectrum was audit and feedback, regular steward- are relatively inexpensive (ceftriaxone recommended in 2% (25/1104) of ship rounds identified unapproved 1 g, $1; vancomycin 1 g, $3) and thus cases and antimicrobial initiation in unit guidelines, provided an accessible are unlikely to offset the cost of the 3% (29/1104). A formal ID consult clinical resource for junior doctors, stewardship team based on saved referral was recommended on 71 raised awareness of appropriate anti- drug costs alone. The antimicrobial occasions (6%). microbial use and reinforced the use of use data used in this study were based In 74% (819/1104) of cases, the rec- the web-based antimicrobial approval on pharmacy purchasing data and ommendation was accepted by the system. Our experience is consistent inpatient stock distribution, with pur- treating team. For most of the unac- with a systematic review of steward- chasing practices likely to have cepted recommendations (233/285; ship programs that suggested that affected use data and to have poten- 82%), no reason was cited for non- restrictive interventions were more tially introduced delays in use trends. acceptance. Where reasons for non- likely to be successful than those based A 2-month worldwide benzylpenicil- acceptance were documented, they only on education or persuasion.9 lin shortage occurred during the study included the use of unapproved unit The interventions that we have period (September–November 2011), protocols (13) and the insistence of a implemented are resource intensive, which may have affected antimicro- more senior doctor in the treating requiring a full-time pharmacist sup- bial use trends at this time. team (14). ported by part-time ID physicians (8– We attempted to reduce potential 10 hours/week). Although a previous adverse effects by using built-in safe- Impact on overall antimicrobial use study has shown a decrease in several guards, including the provision to In the ICU, total broad-spectrum anti- classes of broad-spectrum antimicro- commence antimicrobials without microbial use decreased immediately bials associated with a web-based approval for 24 hours, routinely dis- by 16.6% when the intervention com- approval system only,6 we felt that cussing recommendations with the menced (P < 0.001) (Box 2). The mean without an audit and feedback mech- clinical team, and leaving the final total use of broad-spectrum anti- anism, this intervention would not be decision regarding changes to antimi- microbials fell from 1022 DDD/1000 sustainable. Additionally, postpre- crobial therapy to the treating clini- OBD in the pre-intervention period to scribing audit and feedback recog- cians. We found evidence of greater 937 DDD/1000 OBD in the post- nises that appropriateness of therapy use of -lactam–-lactamase inhibitor intervention period. Before the inter- often needs to be considered on a combinations that offset the vention, the rate of broad-spectrum case-by-case basis, and that broad decreased use of other classes, partic- antimicrobial use did not change; fol- guidelines on prescribing may not be ularly cephalosporins and aminogyl- lowing the intervention, it increased easily applied to individual patients. cosides — a phenomenon termed by 1.0% per month (P < 0.001). Previous studies of similar interven- “squeezing the balloon”. Changes in the use of specific classes tions have found similar patterns of Concerningly, in the ICU we found of antimicrobials are detailed in Box 2 intervention, but on a much less some evidence of a rebound in the and Box 3. intensive scale.10-12 Despite this, only overall use of antimicrobials, and spe- In hospital wards other than the six of 78 respondents in an Australian cifically, in the use of carbapenems, ICU, total broad-spectrum antimicro- survey of hospital fluoroquinolones and glycopeptides. bial use decreased by 9.9% when the reported implementing regular multi- Further work is required to improve intervention commenced (P = 0.002). disciplinary antimicrobial stewardship the quality of prescribing and evaluate The mean total use of broad-spectrum ward rounds.13 longer term effects on antimicrobial antimicrobials fell from 358 DDD/ There are several limitations to this resistance and patient outcomes. 1000 OBD in the pre-intervention observational study. We were unable Acknowledgements: We acknowledge the previous antimicrobial stewardship pharmacists involved in this period to 333 DDD/1000 OBD in the to definitively ascribe changes in pre- project (Jenny Kirschner, Trent Lee) and the members of post-intervention period. Before the scribing to the intervention, due to the Alfred Health Antimicrobial Stewardship Committee.

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