Mass or molar? Recommendations for reporting concentrations of therapeutic drugs

Units used to report any measurement are an integral component of the result. Errors in communication of units have caused catastrophic failures, for example the Mars Climate Orbiter spacecraft crash in 1999.1 One area of laboratory medicine where different units are in common use is therapeutic drug concentrations, where results for the same drug may be reported in either mass units (eg, mg/L) or molar units (eg, μmol/L) by different laboratories, (see Box for a note on the prefix micro [μ]).

Clinical errors may occur if a result in one unit is interpreted using information expressed in a different unit. This situation may occur when a result is separated from its report (for example, telephoned results), or when a clinician is unaware of unit differences when consulting a textbook, journal article, guideline or website. When assessing results in the toxic range it is more likely that external references will be used, as the therapeutic intervals provided on laboratory reports generally do not indicate the severity of possible toxicity. With the rise of health databases where results from more than one laboratory may be combined, uniformity of reporting takes on even greater importance.

A recent publication highlighting variation in units used for reporting drug concentrations,2 as well as reports of patient harm due to misinterpretation of drug concentrations, led to the establishment of a working party (WP) to address this issue.

Recommendation development process

A WP was established by the Royal College of Pathologists of Australasia (RCPA), the Australasian Association of Clinical Biochemists (AACB), the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) and the Royal Australasian College of Physicians. The goal of the WP was to recommend uniform units for reporting drug concentration measurements by pathology laboratories in Australia and New Zealand.

The process adopted by the WP was to systematically identify and evaluate all relevant issues. In assessing information, the WP considered patient safety and clinical decision making to be the most important issues. A discussion paper was developed for consultation and distributed to the parent societies and other interested parties. Over 20 written responses and several verbal responses were received. In light of these responses, the document was revised using a consensus approach. During this period, presentations were also made at the AACB Annual Scientific Conference, the RCPA annual meeting and a combined societies therapeutic drug monitoring workshop. The completed document was then formally endorsed by the four parent bodies represented on the WP.3

Considerations in recommendations

Australian and international recommendations

In 1986 an RCPA broadsheet on the introduction of International System of Units (SI) reporting recommended the use of molar units for reporting therapeutic drug concentrations.4 ASCEPT recommends the use of mass units; however, this recommendation has not been published. The Australian National Measurement Institute (NMI) is responsible for the implementation of SI reporting of units in Australia; however, it offers no specific guidance on the issue of drug measurements in serum. Both mass (kilograms) and amount (moles) are fundamental quantities in the SI system. Standards Australia has no documents related to serum drug concentrations; however, the Australian standard for urine toxicology (AS4308) specifies cut-offs in mass units.5

The issue of units for drug measurements was recently considered at a consensus meeting in the United Kingdom, where it was recommended that mass units be used for routine reporting, with the litre (L) used as the denominator, for all drugs, whether for therapeutic or toxicological purposes.6 Specific exceptions were made for thyroxine, lithium, methotrexate and iron, where molar units were recommended. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and International Union of Pure and Applied Chemistry (IUPAC) specify molar units as the agreed communication terminology for therapeutic drugs.7 The purpose of their standard is not specifically to guide reporting of patient results for clinical use, but to provide unambiguous terminology for data exchange.

There are several important international organisations in the field of medicine regulation that do not have formal recommendations on this topic but generally use mass units in publications covering pharmacokinetic or similar studies. These include the Food and Drug Administration in the United States8 and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.9 Although not specifically related to therapeutic use of drugs, the World Anti-Doping Agency specifies the use of mass units in its relevant documentation.10,11

Units used in published literature, textbooks and other reference sources

In clinical practice, drug measurement results are compared with information from a range of reference sources including journals, textbooks, websites, guidelines and handbooks. These may have been produced locally for use in Australia and New Zealand or sourced from overseas.

A review by the WP of the units used in major journals and textbooks found a wide variation in practice, with a tendency for those produced in the US to use mass units, and for references from other locations, including Australia, to use a combination of mass and molar units, often without internal consistency.3 This variation is not unexpected given the recommendation from the International Committee of Medical Journal Editors, which states: “Drug concentrations may be reported in either mass or SI units, but the alternative should be provided in parentheses where appropriate.”12 It is now common for international textbooks to provide both units for some drugs, at least in a summary table.

The most widely available first-line references for drug information in Australia are the Australian medicines handbook,13 MIMS (http://www.mims. com.au) and the Therapeutic Guidelines series (http://www.tg.org.au/). These works use a mixture of molar and mass units and often both.2 The Therapeutic Goods Administration approves a product information (PI) document for all drugs available in Australia (available through www.ebs.tga.gov.au), which is presented through MIMS and in common software packages for general practitioners, such as Best Practice (Best Practice Software) or Medical Director (Health Communication Network). Another review body, Phoenix Medical Publishing, prepares summaries that are available online through the AusDI online reference tool. The PI and AusDI sections on pharmacokinetics, dosing and toxicity most commonly use mass units, although molar units are also provided for some common drugs.

Current reporting practice

A review of practice in Australia has shown that the concentrations of some drugs are almost always reported in mass units (eg, gentamicin), while those of other drugs are always reported in molar units (eg, lithium and methotrexate). However, for some drugs, both systems are used to a significant extent (eg, phenytoin and paracetamol). Our personal experiences suggest that for some classes of drugs not included in the published study,3 such as immunosuppressants, concentrations are reported almost entirely in mass units, as are those of many specialised drugs measured in dedicated clinical pharmacology laboratories.

In areas outside the routine pathology environment, for example forensic pathology, drug concentrations are routinely reported in mass units.

With regard to international reporting practice, members of the WP sought information from international colleagues on practice in their countries. In the US, mass units are used almost universally, although mL and dL are frequently used as the denominator. In some countries, for example Sweden and Canada, there is a similar situation to that found in New Zealand, with molar units used for a limited number of drugs and mass units used for the remainder. The UK is becoming a consistent user of mass units, with specified exceptions, as their agreed guidelines are implemented.14 The WP did not identify any locations with full or planned use of molar units for all drugs.

Relationship with units used for prescribing drugs

Mass units are almost universally used for describing drug dosages. There are exceptions, such as vitamin D, heparin and insulin, which are prescribed in international units. The dosing unit is relevant to drug reporting when there is a direct relationship between the numerical value of the result and the dose or change in dose prescribed.

In or near the therapeutic range, drug concentrations usually vary in direct proportion to dose and therefore drug dose can be considered relative to the therapeutic range. For example, a drug present at twice the target concentration can be adjusted by halving the dose. The units used for the concentration and the dosing do not need to be aligned for this type of dose adjustment.

However, there are a number of exceptions to this that can cause both within-patient and between-patient variability in drug concentrations:

drug factors such as saturable clearance (eg, phenytoin) or saturable protein binding (eg, valproate);
patient factors such as hypoalbuminaemia (due to liver dysfunction or nephrotic syndrome) or competition with binding sites (due to uraemia or coprescribed drugs); and
higher drug concentrations such as those occurring in overdose.

In these cases the drug concentration may not be directly proportional to drug dose, requiring a more complex application of pharmacokinetics to interpret drug concentrations.

At steady state, drug concentrations are directly related to dose via drug clearance. Physicians and pharmacists are expected to understand this pharmacokinetic relationship, which for parenteral dosing can be described as follows:

maintenance dose = systemic clearance × target concentration at steady state;
similarly, drug concentration after a loading dose is determined by apparent volume of distribution; and
loading dose = volume of distribution × target concentration.

Thus the dose and target concentration are linked by a constant for which reference values can be obtained. When performing calculations it is feasible to convert between units, but the process is simplified when common units are used. Note that the unit of volume used for pharmacological constants such as volume of distribution is the litre, supporting the case for litre to be the volume unit for drug concentrations.

Drugs, prodrugs, metabolites and binding proteins interact on the basis of moles rather than mass. Therefore, it may be expected that reporting in molar concentrations may assist with understanding the relative concentrations of these components. However, as there is variable bioactivity of different metabolites, and the concentration of serum albumin, the most common drug ligand, is reported in mass units, there are significant limitations to the benefits of reporting in molar units for this purpose.

Assay calibration

In order to produce universally comparable results, laboratory assays must use calibrators that are traceable to international reference materials or methods, such as those listed on the database of the Joint Committee for Traceability in Laboratory Medicine,15 or obtained from sources such as the United States Pharmacopeia.16 IFCC and IUPAC guidelines7 and other sources17 provide molecular weights for many drugs for the purposes of conversion between mass and molar units. A limited number of drugs (eg, gentamicin) are mixtures of compounds, and their molecular weight is thus uncertain and may be dependent on the relative abundance of their various components, making assignment of the molar concentrations less reliable.

Some drugs are available in a number of different molecular complexes (eg, hydrates and varying salts). In these cases, when reporting in mass units, it is necessary to define the entity used to standardise the assay. Ideally this should be in the same form as that used to describe the dose of the drug, but it is common laboratory practice to calibrate against a standard based on the free base of the drug. This definition has not been universally adopted for drug dosing, for example phenytoin is referred to as both phenytoin and phenytoin sodium, with the molecular weights of 252 and 274, respectively. Guidance on exact definition of a drug is available from the World Health Organization through the International Pharmacopoeia.18

The use of molar units would reduce the potential for error in assay standardisation by eliminating uncertainty about the molecular form to be used. As assay calibration is generally carried out by trained personnel away from the urgency of acute clinical decision making, this is considered as having lower potential for error. However, there is a need for laboratories and authors to specify the molecular form of any drug used to standardise an assay or prepare a therapeutic dose.

Other factors

Some substances used therapeutically are also endogenous compounds that are measured for purposes other than therapeutic monitoring and toxicology. Examples include the hormones cortisol (nmol/L), testosterone (nmol/L) and thyroxine (pmol/L), the minerals iron (μmol/L) and calcium (mmol/L), and the vitamins B12 (pmol/L) and D (nmol/L). For these and other endogenous compounds, the units used for reporting these analytes should be the same regardless of endogenous or exogenous origin.

Conclusions and overall recommendations

The WP has concluded that it is important that serum concentrations for any drug are reported with one unit throughout Australia and New Zealand irrespective of the location of the laboratory or the purpose of the measurement. The aim is to avoid patient harm that may occur if a result is interpreted against a decision point reported in different units. We recommend the use of mass units for reporting drug concentrations, except where there are specific reasons for the use of other units for a specific therapeutic agent.

Although the only published Australasian recommendation, which dates from 1986, recommended molar units, the recommendation was followed by the statement that “It is rational and possibly a long term expectation that drugs also will be labeled and administered in molar terms”.3 As drug dosing remains in mass units, without movement for change, it is appropriate to review this recommendation. The UK consensus is particularly relevant to the current situation as it relates directly to pathology reporting, is the product of wide consultation, is in a similar clinical context and has been produced recently.

Supporting information in the form of textbooks, journal articles, websites and guidelines tends to follow the common usage in the country of origin. As the US and UK are the major English language sources of information, it is likely that the predominance of mass units in these sources will become further entrenched. The officially approved PI used in Australia predominantly uses mass units, although some documents also use molar units in selected sections.

In circumstances where calculations are used to predict dose based on serum concentration, using the same units for both components removes the risk due to conversion between units.

There are drugs for which units other than mass units are preferred because of universal usage of these units in laboratories and supporting information. These are:

lithium (mmol/L);
methotrexate (μmol/L);
thiopurine metabolites (pmol/109 red blood cells); and
drugs for which molar units are uniformly used locally and internationally in laboratories and supporting information.

For all drugs that are also present endogenously (including hormones, minerals and vitamins used therapeutically), we recommend the same unit as is used for routine clinical measurement.

We recommend that the litre should be the denominator for reporting drug concentrations unless there are specific reasons for using other units. In summary, the reasons for this recommendation are as follows. The litre is the SI unit for volume, is used for most other laboratory concentration measurements, and is commonly used for physiological volumes such as extracellular fluid volume and for volume of distribution.

The recommendations presented here are consistent with a wider project by the RCPA to standardise units of reporting for all pathology tests in Australia.19

Use of the prefix micro (μ)

The Royal College of Pathologists of Australasia has recently adopted as policy the use of u, rather than the Greek letter μ, for the expression of “micro” in units for reporting pathology results (eg, ug/L rather than μg/L for micrograms per litre). This is to ensure the safe transmission of the unit to different computer systems and printers, including those with a limited character set, and also to ensure consistency with the adoption of the Unified Code for Units of Measure (UCUM) system for the unambiguous electronic transmission of units.

Is there really misuse and abuse of dabigatran?

A brief commentary on the RE-LY study

Appropriate and optimal anticoagulation for the increasing number of Australians with non-valvular atrial fibrillation (AF) remains a challenge. If achieved, it would substantially reduce the burden of disabling and fatal AF-related stroke.

Four large randomised controlled trials (RCTs) have reported that the direct thrombin inhibitor, dabigatran etexilate, and the direct activated factor X (Xa) inhibitors, rivaroxaban and apixaban, are at least as efficacious and safe as warfarin, and apixaban is superior to aspirin, in a broad range of individuals with non-valvular AF.1–5 On the basis of these results, regulators have approved dabigatran in more than 75 countries, including Australia, and guidelines suggest that the new oral anticoagulants are preferable to warfarin for most patients with non-valvular AF.6–9

Patient selection in the RE-LY trial

The RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial of dabigatran versus warfarin included patients with all degrees of risk of stroke and systemic embolism.9 If the trial had excluded participants with a low risk, ie, a CHADS2 score of 1 (congestive heart failure, hypertension, age ≥ 75 years, diabetes, 1 point each; prior stroke or transient ischaemic attack, 2 points), clinicians would not now know that these patients derive benefit from dabigatran compared with warfarin.

Quality of anticoagulation control

RE-LY trial participants who were assigned warfarin had a median time in therapeutic range (TTR) of 67%. This may have led to an underestimate of the benefits of dabigatran compared with warfarin in community practice, where the median TTR for patients taking warfarin is rarely this high.

Benefits of dabigatran

Dabigatran (150 mg twice daily) compared with warfarin produced reductions in ischaemic stroke (one-third)
and haemorrhagic stroke (one-half) that were statistically significant and clinically important. The reduction in stroke with dabigatran was also evident in the very elderly, participants with renal impairment, participants with previous myocardial infarction (MI) or stroke, and in the presence and absence of aspirin.

Safety of dabigatran

Both doses (110 mg or 150 mg twice a day) of dabigatran were associated with significantly lower life-threatening and fatal bleeding than warfarin. Among participants aged ≥ 75 years, extracranial bleeding risk was similar or higher with both doses of dabigatran compared with warfarin, whereas intracranial bleeding risk was lower with both doses of dabigatran.10 In participants aged < 75 years, both doses of dabigatran were associated with lower risks of both intracranial and extracranial bleeding than warfarin.

Participants who were taking dabigatran also had lower rates of bleeding if they required urgent or emergency surgery than those taking warfarin, despite access
to vitamin K and clotting factors that could pharmacologically reverse the anticoagulant effect
of warfarin.11 Although there is no specific antidote
for dabigatran, the case-fatality rate of intracranial haemorrhage was not significantly different in participants assigned dabigatran or warfarin.12

The absolute increase in MI with dabigatran compared with warfarin was 0.14%–0.17% per year. This was outweighed by a 0.6% per year reduction in stroke and systemic embolism.13 Adding aspirin to dabigatran did not protect against any increased risk of MI, but increased bleeding.

Real world experience with dabigatran

Recent postmarketing surveillance by the European Medicines Agency and the United States Food and Drug Administration (FDA) found no evidence of excess serious bleeding with dabigatran compared with warfarin.14,15

We have a continued responsibility to ensure that the favourable effects of new anticoagulants compared with warfarin demonstrated in RCTs are translated into clinical practice. Ongoing Phase IV safety surveillance, economic analysis, and doctor and patient education are key to this process.

Meanwhile, optimal safety and effectiveness of the new oral anticoagulants in routine clinical practice demand appropriate selection of patients (eg, estimated glomerular filtration rate ≥ 30 mL/min) and dose, a high level of adherence, regular monitoring of renal function (which may deteriorate in at-risk patients) and appropriate periprocedural management of anticoagulation interruption for invasive procedures. As treatment with
a new oral anticoagulant is not suitable for all patients, warfarin will retain an important role in the management of patients who can maintain excellent anticoagulant control, as well as those with severe renal impairment and other contraindications to the new oral anticoagulants.

The pricing of statins and implications for Pharmaceutical Benefits Scheme expenditure

To the Editor: Following two articles in the Journal,1,2 I wish to provide an update on the pricing of statins in Australia and the implications for Pharmaceutical Benefits Scheme (PBS) expenditure. I was prompted to do so by a recent review by the Pharmaceutical Benefits Advisory Committee (PBAC), which was instigated by the Senate when it passed legislation enabling the current pharmaceutical pricing arrangements.3 The purpose of the review was to determine if there was new evidence on whether rosuvastatin and atorvastatin should be included in the existing statins therapeutic group.

A summary of the PBAC review, which was released publicly in August 2012, reaffirmed previous recommendations that atorvastatin and rosuvastatin are more effective than simvastatin in lowering cholesterol levels.4 It also noted that the current evidence did not change the PBAC’s previous advice that only an average price differential of 12.5% between atorvastatin and simvastatin was acceptable.4 This has important implications, as the ex-manufacturer price of simvastatin has fallen significantly following the first round of price disclosure to between $9 (20 mg) and $19 (80 mg),5 thus increasing the price differential. Unfortunately, the recent 25% voluntary cut in the price of atorvastatin by the manufacturers is not sufficient to meet the PBAC recommendation. The ex-manufacturer price of the most commonly prescribed dose of atorvastatin (40 mg) fell from $51 to $38 on 1 December 2012, but the price for determining PBS subsidy that the PBAC would consider acceptable (assuming that it is set at the average recommended differential) would be around $21. Applying the PBAC recommendations in full would save taxpayers and consumers about an additional $260 million annually (calculated by applying PBAC recommended prices to the quantities of each dose of atorvastatin and rosuvastatin prescribed on the PBS in 2011–12).

But even if the PBAC recommendations for atorvastatin pricing were implemented, the cost in Australia would be many times higher than other comparable countries (eg, patients in New Zealand currently pay less than A$2 per month). Similar international price differentials now exist for several other therapies for which patents have recently expired (Box). This emphasises the need for substantial reform of the current pricing policies to ensure value for money when purchasing pharmaceuticals through the PBS.

International price comparison of ex-manufacturer prices of selected therapies*

* Data were obtained from the Pharmaceutical Benefits Scheme (Australia), Pharmaceutical Services Negotiating Committee (Category M) (England), the Dental and Pharmaceutical Benefits Board (Sweden) and the Pharmaceutical Management Agency (PHARMAC) (New Zealand). Comparisons are based on average exchange rates between the 2010 and 2012 calendar years. † Price of atorvastatin in Australia takes into account the 25% price reduction that occurred on 1 December 2012.

Prescribing trends before and after implementation of an antimicrobial stewardship program

Up to 50% of antimicrobial agents prescribed to hospital inpatients are considered to be inappropriate,1,2 and this excess use has been associated with increased mortality, adverse drug reactions and the development of resistant bacteria.3,4 The Australian Commission on Safety and Quality in Health Care recently published recommendations for hospital-based antimicrobial stewardship programs.2 A variety of approaches are available to implement these recommendations, including dissemination of guidelines, education, restricting antimicrobial availability and postprescribing audit and review.

We aimed to evaluate changes in antimicrobial prescribing after the implementation of an antimicrobial stewardship program in a specialist tertiary referral hospital.

Methods

Setting

Alfred Health is a health service comprising three hospitals in metropolitan Melbourne. The largest campus, the Alfred Hospital, is a 430-bed tertiary teaching hospital with medicine, surgery and trauma services. It includes immunocompromised populations (including patients with HIV, cystic fibrosis and heart/lung transplantation, and haematology and bone marrow transplantation) and is supported by a 35-bed intensive care unit (ICU).

Antimicrobial stewardship program

We have previously described the preliminary activities of the antimicrobial stewardship team.5 A web-based antimicrobial approval system (Guidance MS, Melbourne Health) was rolled out from October 20106 and a full-time pharmacist was appointed in January 2011. Before this, authorisation to prescribe restricted antimicrobial agents required approval from infectious diseases (ID) registrars, but auditing had suggested poor compliance. In the new system, online approval could be obtained to use restricted antimicrobials for pre-approved indications that were included in national or local consensus guidelines. Short-term approval was granted for other indications specified by the clinician (non-standard indications). Pharmacists could alert the antimicrobial stewardship team of unauthorised antimicrobial use exceeding 24 hours (pharmacist alerts).

Non-ICU antimicrobial stewardship ward rounds (by the stewardship pharmacist and either an ID registrar and/or an ID physician, on weekdays) commenced in January 2011. Each round comprised a focused review of clinical notes and results of investigations aimed at establishing the indication, planned duration, appropriateness, and alternatives to the use of restricted antimicrobial agents. Recommendations were discussed with the treating team and documented in writing; the final decision regarding patient management was the responsibility of the treating team. Patients who required more in-depth management advice were referred to the ID consult service.

Patients were reviewed by the stewardship team if they were receiving at least one restricted antimicrobial for a non-standard indication, where approval had expired, or where a pharmacist alert had been created. At our hospital, 13 restricted antimicrobial agents require web-based approval: amikacin, azithromycin, cefepime, ceftazidime, ceftriaxone, ciprofloxacin, meropenem, moxifloxacin, piperacillin/tazobactam, teicoplanin, ticarcillin/clavulanate, tobramycin and vancomycin. Patients were not reviewed by the antimicrobial stewardship team if they had already received a formal ID consult, or were admitted under lung transplant/cystic fibrosis, haematology and bone marrow transplant, or burns services, where ID physicians performed regular ward rounds (Box 1).

For several years in the ICU, the microbiology registrar has discussed results and antimicrobial treatments with ICU teams daily (supported by an ID physician three times per week). The stewardship pharmacist augmented this from January 2011 with all patients reviewed routinely. In December 2010, there was also a change to empirical ICU guidelines for health care-acquired sepsis, from ticarcillin/clavulanate or cefepime (for early and late sepsis, respectively) to piperacillin/tazobactam (regardless of onset), in all cases combined with an aminoglycoside, except when combined with quinolone in specified situations. Recommendations for vancomycin use did not change.

Outcome measures

We compared trends in the rate of use of antimicrobial classes before stewardship implementation (January 2008 to December 2010) and after implementation (January 2011 to June 2012). Antimicrobial consumption quantities were converted into defined daily doses (DDD) per 1000 occupied bed-days (OBD) as part of the National Antimicrobial Utilisation Surveillance Program.7,8 Total broad-spectrum antimicrobial use was defined as the sum of usage for all classes except for aminoglycosides, which are regarded as narrow-spectrum antibiotics. Antimicrobial use is based on pharmacy purchasing data and inpatient stock distribution (excluding hospital in the home and the emergency department). Outcomes were assessed by:

the mean rate of antimicrobial use in the intervention period compared with the pre-intervention period;
model-predicted immediate change in antimicrobial use between the end of the pre-intervention period and the commencement of the intervention period (immediate change);
model-predicted change in the rate of antimicrobial use between the pre-intervention period and post-intervention period (change in trend);
the immediate change and the change in trend in antimicrobial use were both assessed using segmented Poisson regression.

We defined a clinically significant decrease in antimicrobial use as:

a statistically significant (P < 0.05) immediate decrease in the rate of antimicrobial use; and/or
a statistically significant decrease in the rate of change of antimicrobial use in the intervention period compared with the pre-intervention period.

Statistical tests were performed using Stata version 12 (StataCorp). Ethical permission to review these data was obtained from the Alfred Health Human Ethics Committee.

Results

Impact of antimicrobial stewardship rounds

Between 10 January 2011 and 30 June 2012, 2254 patients were identified as requiring review by the antimicrobial stewardship team. An antimicrobial management recommendation was made in 779 of 2254 (35%) patients, with a total of 1104 recommendations made. Of the patients for whom a recommendation was made, the median age was 66 years (range, 16–98 years) and 503 (65%) were male.

Recommendations were made in patients under 26 different treating units; 63% (490/779) of patients were managed by surgical/trauma units and 37% (289/779) were medical patients. The median duration of antimicrobial therapy before review was 2 days (interquartile range, 1–4 days). The majority of recommendations were made following pharmacy alerts (907/1104; 82%), by non-standard approvals (92/1104; 8%) or based on expiry of the current antimicrobial approval (93/1104; 8%).

Recommendations were made to modify treatment for patients on restricted broad-spectrum antimicrobials; most commonly, ceftriaxone (278), piperacillin/tazobactam (155), ciprofloxacin (99) and vancomycin (96).

In 40% (440/1104) of recommendations, antimicrobial discontinuation was suggested; in an additional 11% (123/1104), antimicrobial de-escalation was recommended; and in 13% (145/1104), an intravenous to oral switch was recommended. Escalation of antimicrobial spectrum was recommended in 2% (25/1104) of cases and antimicrobial initiation in 3% (29/1104). A formal ID consult referral was recommended on 71 occasions (6%).

In 74% (819/1104) of cases, the recommendation was accepted by the treating team. For most of the unaccepted recommendations (233/285; 82%), no reason was cited for non-acceptance. Where reasons for non-acceptance were documented, they included the use of unapproved unit protocols (13) and the insistence of a more senior doctor in the treating team (14).

Impact on overall antimicrobial use

In the ICU, total broad-spectrum antimicrobial use decreased immediately by 16.6% when the intervention commenced (P < 0.001) (Box 2). The mean total use of broad-spectrum antimicrobials fell from 1022 DDD/1000 OBD in the pre-intervention period to 937 DDD/1000 OBD in the post-intervention period. Before the intervention, the rate of broad-spectrum antimicrobial use did not change; following the intervention, it increased by 1.0% per month (P < 0.001). Changes in the use of specific classes of antimicrobials are detailed in Box 2 and Box 3.

In hospital wards other than the ICU, total broad-spectrum antimicrobial use decreased by 9.9% when the intervention commenced (P = 0.002). The mean total use of broad-spectrum antimicrobials fell from 358 DDD/1000 OBD in the pre-intervention period to 333 DDD/1000 OBD in the post-intervention period. Before the intervention, the rate of broad-spectrum antimicrobial use increased by 0.1% per month; following the intervention, it increased by 0.3% per month (P = 0.49). Changes in the use of specific classes of antimicrobials are detailed in Box 2 and Box 3.

Discussion

The antimicrobial stewardship program brought immediate reductions in the use of total broad-spectrum antimicrobials, particularly third/fourth generation cephalosporins and glycopeptides. In addition to case-by-case audit and feedback, regular stewardship rounds identified unapproved unit guidelines, provided an accessible clinical resource for junior doctors, raised awareness of appropriate antimicrobial use and reinforced the use of the web-based antimicrobial approval system. Our experience is consistent with a systematic review of stewardship programs that suggested that restrictive interventions were more likely to be successful than those based only on education or persuasion.9

The interventions that we have implemented are resource intensive, requiring a full-time pharmacist supported by part-time ID physicians (8–10 hours/week). Although a previous study has shown a decrease in several classes of broad-spectrum antimicrobials associated with a web-based approval system only,6 we felt that without an audit and feedback mechanism, this intervention would not be sustainable. Additionally, postprescribing audit and feedback recognises that appropriateness of therapy often needs to be considered on a case-by-case basis, and that broad guidelines on prescribing may not be easily applied to individual patients. Previous studies of similar interventions have found similar patterns of intervention, but on a much less intensive scale.10–12 Despite this, only six of 78 respondents in an Australian survey of hospital pharmacies reported implementing regular multidisciplinary antimicrobial stewardship ward rounds.13

There are several limitations to this observational study. We were unable to definitively ascribe changes in prescribing to the intervention, due to confounders such as concurrent changes in ICU empirical treatment guidelines. Aggregated data on antimicrobial use is not able to provide a measure of appropriateness of use and does not account for changes in antimicrobial dosing. The data on antimicrobial use includes units known to be high users of broad-spectrum antimicrobials (eg, cystic fibrosis) but where the only new intervention was the introduction of the web-based approval system. A formal cost-effectiveness study was not undertaken; however, we note that the antimicrobial classes where significant decreases in use were seen are relatively inexpensive (ceftriaxone 1 g, $1; vancomycin 1 g, $3) and thus are unlikely to offset the cost of the stewardship team based on saved drug costs alone. The antimicrobial use data used in this study were based on pharmacy purchasing data and inpatient stock distribution, with purchasing practices likely to have affected use data and to have potentially introduced delays in use trends. A 2-month worldwide benzylpenicillin shortage occurred during the study period (September–November 2011), which may have affected antimicrobial use trends at this time.

We attempted to reduce potential adverse effects by using built-in safeguards, including the provision to commence antimicrobials without approval for 24 hours, routinely discussing recommendations with the clinical team, and leaving the final decision regarding changes to antimicrobial therapy to the treating clinicians. We found evidence of greater use of β-lactam–β-lactamase inhibitor combinations that offset the decreased use of other classes, particularly cephalosporins and aminogylcosides — a phenomenon termed “squeezing the antibiotic balloon”. Concerningly, in the ICU we found some evidence of a rebound in the overall use of antimicrobials, and specifically, in the use of carbapenems, fluoroquinolones and glycopeptides. Further work is required to improve the quality of prescribing and evaluate longer term effects on antimicrobial resistance and patient outcomes.

1 Existing infectious diseases services and antimicrobial stewardship interventions introduced during the study

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

	Before intervention		After intervention		Change
Antimicrobial class/setting	Use*	Trend (%/month)†	Use*	Trend (%/month)†	Change in use†	Immediate change (95% CI)‡	Change in trend (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 β-lactam–β-lactamase inhibitor	129.1	0.3%	191.3	0.6%	48.2%	34.2% (21.8%, 47.9%)	0.3% (− 0.5%, 1.1%)
Carbapenems	113.8	0.4%	133.9	2.4%	17.6%	− 11.2% (− 20.7%, − 0.6%)	2.1% (1.2%, 3.0%)
Cephalosporins (3rd/4th generation)	219.2	0.8%	131.2	1.6%	− 40.2%	− 54.6% (− 59.0%, − 49.7%)	0.8% (− 0.1%, 1.7%)
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 β-lactam– β-lactamase inhibitor	50.5	− 0.4%	54.5	1.9%	8.1%	− 2.9% (− 18.5%, 15.7%)	2.3% (0.9%, 3.7%)
Carbapenems	52.9	− 0.4%	53.5	0.1%	1.0%	6.7% (− 10.0%, 26.5%)	0.5% (− 0.9%, 2.0%)
Cephalosporins (3rd/4th generation)	90.1	0.5%	80.3	0.7%	− 10.9%	− 22.4% (− 32.3%, − 11.1%)	0.2% (− 1.0%, 1.4%)
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.

3 Antimicrobial use before and after implementation of the antimicrobial stewardship ward rounds, by class of antimicrobial agent

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.