Appropriate use of restricted antimicrobial agents in hospitals: the importance of empirical therapy and assisted re-evaluation

Marie Thuonga, Frédérique Shortgena, Virginie Zazempab, Emmanuelle Giroud, Claude J. Soussyc and Christian Brun-Buissona,d,*

a Medical Intensive Care, b Hospital Pharmacy, c Clinical Microbiology Laboratory and d Infection Control Unit, Hôpital Henri Mondor, Créteil, France

Abstract

We evaluated the appropriateness of use of restricted antimicrobial agents in the context of a newly implemented order form and delivery system for restricted antimicrobial agents, using sequential prospective audits of prescriptions. Four antimicrobial agents were selected: glycopeptides (61 prescriptions), ciprofloxacin (42), piperacillin–tazobactam (42) and imipenem– cilastatin (47). The justification and adequacy of the antibiotic or combination used, reassessment of therapy and duration of treatment were appraised with reference to the clinical situation and hospital's guidelines. Of the 192 prescriptions, 30 (16%) were empirical therapy, 95 (49%) empirical and secondarily documented and 67 (35%) initially documented therapy. Overall, 73% of prescriptions conformed to guidelines, but the adequacy varied from 93% for vancomycin to only 38% for ciprofloxacin. Of 83/157 initially inadequate prescriptions, 42 (51%) were switched according to guidelines, but only 14% of ciprofloxacin prescriptions were adapted later. An intervention audit with counselling on ciprofloxacin usage increased this rate to 75%. Although implementation of the guidelines resulted in a marked reduction in overall antimicrobial costs, inappropriate antibiotic usage may persist for some drugs despite restricted access. These results emphasize the need for combined interventions using education and expert counselling, targeted to classes of antibiotic for which inappropriate usage is most common.

Introduction

Because of increasing concern and awareness of antibiotic resistance problems worldwide and frequent inappropriate use of antimicrobial agents in hospitals,1,2 these drugs have often been the target of attempts to restrict and control their use.25 One common measure is to adopt an antibiotic formulary. At our hospital, the Drug and Therapeutics Committee has fostered an antibiotic policy since the early 1980s. The policy includes an antibiotic formulary, based on a classification of antimicrobial agents into four groups of increasingly restricted access and control, according to their indications for use, potential adverse effects and costs. The formulary and guidelines have been updated periodically by consensus between clinicians, microbiologists and pharmacists.

In May 1996, the delivery of antimicrobial agents on the restricted list was further controlled by introducing a new restrictive order form,6 which resulted in a substantial reduction of overall prescribing and costs of controlled antimicrobial agents. In this context, we wished to assess the appropriateness of use of some of these antimicrobial agents, selected for their high prescription volume or potential ecological impact (the glycopeptides vancomycin and teicoplanin, ciprofloxacin, piperacillin–tazobactam and imipenem–cilastatin), and for which specific guidelines had been developed.

Materials and methods

Hospital setting and antibiotic policy

Henri Mondor Hospital is a 960-bed, university, referral and tertiary-care hospital with 25000 admissions/year. Antibiotics in groups 1 and 2 of the antibiotic formulary are those with unrestricted prescribing, including first-line antimicrobial agents (such as penicillin G, oxacillin, amoxycillin or macrolides). Antibiotics in groups 3 and 4 are restricted (listed in Appendix). Those in group 3 are generally more costly broad-spectrum agents, recommended for therapy of nosocomial infections and/or infections caused by organisms with expected or documented resistance to antimicrobial agents in groups 1 and 2; those in group 4, such as glycopeptides, are restricted for use in specific indications. Practice guidelines are available for the choice of drugs within each group, and for usage of specific drugs on the restricted list (glycopeptides, fluoroquinolones, piperacillin–tazobactam, imipenem–cilastatin and aminoglycosides).

Recently, this policy has been reinforced by introducing an order form, based on one previously used at our institution for ordering tumour marker tests.6 This form (see Appendix) provides information on daily dosage and costs of therapy for the 23 antimicrobial agents on the restricted list. It discourages the use of some of these drugs as prophylactic or empirical therapy, according to the hospital's guidelines. Orders are checked upon receipt by pharmacists for consistency with guidelines and recommended usual daily dosage; any departure from these guidelines must be justified, if necessary by direct liaison with the prescribing physician. Suggestions are provided for alternative choices when appropriate, and to avoid unduly prolonged therapy or for shifting to the oral formulation whenever possible.

Antibiotic audits

To evaluate the appropriateness of antibiotic prescribing within the context of the new antibiotic delivery system, we selected four antimicrobial agents of different classes which were among those most often prescribed and/or the most expensive to the hospital's pharmacy: glycopeptides (vancomycin and teicoplanin), ciprofloxacin, piperacillin– tazobactam and imipenem–cilastatin.

The pharmacist notified one of the assessors within 48 h after a patient had been prescribed one of the drugs under study. All prescriptions delivered for therapy of suspected or documented infection, except for patients in the haematology and the haemodialysis units (where specific therapeutic protocols are used for drugs included in this survey) were included in the study. Assessors were senior physicians with expertise in infectious diseases. They collected relevant clinical and microbiological data available when therapy began, using a standardized form, as well as follow-up information from 3–5 days after the start of therapy until the end of the antibiotic course. The appropriateness of antibiotic usage was assessed according to the following criteria. (i) Justification of antibiotic prescribing: given the clinical situation and microbiological information at that time, was there a need for a new antibiotic prescription? (ii) Adequacy of initial antibiotic choice: did the antibiotic(s) selected conform to the hospital's guidelines?; if not, was there an acceptable justification for such prescribing? (for example, iv ciprofloxacin should be restricted to patients with an infection caused by documented or suspected resistant Gram-negative bacteria, or Pseudomonas aeruginosa; vancomycin should be used for patients with suspected or documented infection caused by methicillin-resistant staphylococci, or for therapy of infections caused by Gram-positive bacteria in patients allergic to ß-lactams; teicoplanin was only used when there were adverse effects with vancomycin, or when iv access was not possible). (iii) If a combination was prescribed, was such therapy justified based on the severity of sepsis, the site of infection or microbiological criteria (e.g. organisms at risk of selection or emergence of resistance)? (iv) If prescribed, was the combination selected adequate for the infection so treated? (v) Was the duration of therapy adequate? (vi) Re-evaluation and adaptation of therapy: the assessors examined whether treatment was re-evaluated after receipt of susceptibility data and whether a switch to an antibiotic of a preceding group or to oral therapy was made when appropriate, within an acceptable delay from documentation of infection (i.e. <=5 days after initiation of therapy, representing the expected delay from institution of therapy to receipt of the relevant microbiological information and evaluation of initial response to therapy).

Criteria (i) to (iv) were evaluated when therapy began and 4–6 days later. When difficulties in interpretation were encountered by assessors, a second opinion was sought from a senior member of the antibiotic committee; any disagreements were resolved by consensus.

In parallel, the pharmacists developed a database analysis program to quantify antibiotic use, recording the number of doses per day and the expenditure for each antibiotic.

To analyse the appropriateness of prescribing, antibiotic prescriptions were grouped into three categories: (i) empirical therapy, including all prescriptions given in the absence of microbiological documentation throughout the antibiotic course; (ii) empirical–secondarily documented (referred to as ‘empirical/documented’), which includes all antibiotic courses that were initiated empirically, but were subsequently associated with microbiologically documented infection, whether the initial antibiotic choice was maintained or modified; (iii) documented infections, with full documentation of infection and identification of a likely pathogen available at the start of therapy.

During the first part of the study (the ‘observational audit’, May–October 1996), assessors did not interfere with physicians' prescribing. Glycopeptides and ciprofloxacin were audited in the first 3 months, and the other two drugs in the following period. In a second period (‘intervention audit’, July–November 1997), after having reviewed the results of the observational audit, assessors suggested alternative choices when ciprofloxacin prescriptions were considered inappropriate.

Statistical analysis

Patterns of individual drugs prescriptions and differences between the two audited periods were compared using the {chi}2 test, with Yates' correction when appropriate.

Results

Observational audit

Antibiotic prescriptions.
During this period, there were 192 prescriptions for the four antimicrobial agents surveyed, in 188 patients. Overall, 15% of antibiotic courses were administered for therapy of severe sepsis and 13% for septic shock; 52 (27%) patients were bacteraemic (Table IGo). Two-thirds (125) of the prescriptions were initiated empirically, of which 95 (74%) were empirical/documented and 30 (26%) remained empirical (Table IGo). Among the four drugs surveyed, vancomycin or piperacillin–tazobactam were more often prescribed empirically than ciprofloxacin or imipenem (75% and 51% respectively; P < 0.05). Except for ciprofloxacin therapy, most infections treated were hospital-acquired. Altogether, 162/192 (84%) prescriptions were eventually associated with microbiologically documented infection. The FigureGo shows the distribution of the major microorganisms eventually identified in patients with documented infection treated with imipenem, piperacillin–tazobactam or ciprofloxacin.


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Table I. Characteristics and adequacy of 192 prescriptions for the four restricted antibiotics audited
 


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Figure. Distribution of organisms documented during therapeutic courses with ciprofloxacin ({blacksquare}), piperacillin–tazobactam ({square}) or imipenem ({blacksquare}). K.E.S., Klebsiella, Enterobacter and Serratia spp.

 
Justification and appropriateness of initial antibiotic therapy.
Overall, administration of antibiotics was considered justified in 96% of patients, given the clinical context, but the initial antibiotic choice was considered appropriate for only 73% (Table IGo). Vancomycin was appropriately prescribed in most cases (93%), whereas only 38% of initial ciprofloxacin prescriptions were considered appropriate. The most common reasons for inadequacy of ciprofloxacin usage were the lack of suspicion of infection caused by P. aeruginosa or resistant Enterobacteriaceae, and availability of a more appropriate and/or less broad-spectrum agent for the anticipated or documented pathogen(s), according to the hospital's guidelines.

Analysis of the adequacy of prescriptions restricted to cases with initially documented infection shows even more striking differences between the four drugs audited. Glycopeptides, imipenem and piperacillin–tazobactam were prescribed appropriately in 93%, 70% and 60% of such cases, respectively, while only five of 19 (26%) ciprofloxacin prescriptions conformed to guidelines, given the clinical and microbiological information available (Table IIGo). Ciprofloxacin was mostly prescribed for treatment of community-acquired urinary tract (24%) or lower respiratory tract infections (17%) and nosocomial intra-abdominal infections (17%); most of the inappropriate prescriptions were in cases of community-acquired urinary tract or lower respiratory tract infection.


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Table II. Adequacy of initial prescriptions and change of therapy according to documentation of infection
 
Treatment re-evaluation and adaptation of therapy.
Seven patients could not be re-evaluated because of early discharge or transfer, so 28/30 (93%) empirical antibiotic courses and 157/162 (97%) empirical/documented or documented prescriptions were re-evaluated 3–5 days after initiation of therapy.

Most antibiotic courses remaining empirical were not modified, regardless of their initial appropriateness (Table IIGo). Overall, 89 (57%) of the 157 courses prescribed for initially or secondarily documented infections were inadequate (all except three requiring substitution of another narrower-spectrum agent). In the 90 empirical/documented antibiotic courses, therapy was adapted in 39 (68%) of the 56 initially inadequate empirical therapy. The rate of adaptation was 89% for piperacillin–tazobactam, 80% for vancomycin, 78% for imipenem and only 29% for ciprofloxacin. In the 67 documented infections that could be re-evaluated, therapy was changed in approximately three-quarters of patients initially administered imipenem or piperacillin–tazobactam, resulting in an overall final adequacy rate of 87% and 80%, respectively. Inadequate ciprofloxacin prescriptions remained unchanged. The three microorganisms causing most of the infections in patients administered ciprofloxacin (FigureGo) were methicillinsusceptible staphylococci (17%), amoxycillin-susceptible Escherichia coli (19%) and P. aeruginosa (14%). The overall final adequacy rate for ciprofloxacin prescriptions was therefore only 40%, compared with 92% for vancomycin, and 83% and 82% for piperacillin–tazobactam and imipenem, respectively (Table IIGo).

Evaluation of combination therapy.
An antibiotic combination was initially administered in 114 (59%) courses (Table IIIGo). Re-evaluation showed that the combination selected was the least often adequate (48%) in patients given vancomycin (e.g. a combination of vancomycin and amikacin for methicillin- and aminoglycoside-resistant Staphylococcus aureus infection), and most often adequate (74%) in patients given piperacillin–tazobactam.


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Table III. Adequacy of initial combination therapy and later change of therapy according to documentation of infection
 
Intervention audit

Because of the unsatisfactory results regarding the adequacy of ciprofloxacin, we tested the effect of an intervention using counselling and validation of all prescriptions by a senior referring physician, during two 1 month periods (15 June to 15 July 1997 and 15 September to 17 October 1997). Compared with the same period during the observational audit (15 September to 15 October 1996), there was a 62% decrease in new ciprofloxacin orders (16 versus 42). The distribution of prescriptions among empirical and documented cases was similar to the first period, with 13%, 25% and 62% for empirical, empirical/documented and documented therapy, respectively. Although ciprofloxacin was administered more often for urinary tract infections (56% versus 24%), and less frequently for therapy of infections caused by S. aureus (6% versus 28%), the appropriateness of initial prescribing had not improved, with only five (31%) of 16 orders being appropriate. Almost half (three of seven) intravenous ciprofloxacin courses could have been administered by the oral route. Liaison with the prescribing physician 2–4 days after the initial order led to a change in therapy in 12/16 cases, including use of an alternative therapy in nine patients or switch to the oral route in one patient, and to increasing ciprofloxacin dosage in one patient with P. aeruginosa infection.

Antibiotic consumption and costs

Except for piperacillin–tazobactam, the use of which increased slightly in the 2 years after it was marketed and introduced into the formulary, the total hospital consumption of the three other drugs decreased markedly during that period (Table IVGo), even though the number of discharges did not decrease substantially. The associated savings to the hospital pharmacy amounted to 2.5 million French francs (FF) (£250000) after implementation of the new system, 84% of which was caused by a reduction in usage of restricted antimicrobial agents. One-third of these savings resulted from a reduction in consumption of the four drugs surveyed.


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Table IV. Yearly consumption of the four antibiotics audited during the 3 year period before and after implementation (in May 1996) of the new delivery system
 
Discussion

Previous studies evaluating antibiotic use in hospitals have shown that up to 50% of prescriptions can be inappropriate.3,79 However, improving antibiotic usage in hospitals is a challenging task that raises complex issues.1,5,10 Approaches taken include educational programmes, development of a restrictive hospital formulary, limitation on reports of sensitivity tests, regulation of interactions between pharmaceutical representatives and physicians, controlled distribution, automatic stop-orders and written justification for specific antimicrobial agents and/or requirement for expert approval before or after prescribing some drugs.1,4,11 While, in many studies, evaluation of interventions has focused on the reduction in the volume and costs of antimicrobial agents, few have documented the effect of such interventions on the appropriateness of antibiotic use.11,12 It is often difficult to know which of the specific interventions has been helpful in improving antibiotic usage, since several steps are often taken simultaneously.13

The introduction of the new restrictive order form and delivery system at our hospital resulted in a sharp decrease in the total amount of restricted antimicrobial agents prescribed (Table IVGo) and in substantial savings to the hospital's pharmacy budget. We were interested to examine whether these changes were associated with high rates of appropriate use. Our prospective observational audit of a sample of four antimicrobial agents showed that a relatively high proportion of prescriptions (74%) proved eventually adequate. However, substitution according to guidelines eventually occurred in only 45 (51%) of 89 prescriptions requiring such changes. The majority of inadequate prescriptions were for ciprofloxacin, which led to an intervention audit with re-evaluation and direct counselling.

The different results recorded for the four drugs targeted in our study is striking. The rather high appropriate use of glycopeptides deserves some comments. When our controlled antibiotic policy was first reinforced in 1992, appropriate use of glycopeptides (vancomycin and teicoplanin) was targeted. Recent concerns about the emergence of resistance in Gram-positive cocci at our hospital14 was a strong incentive for controlling glycopeptide use. Specific recommendations were made, reducing their recommended indications and markedly restricting the indications for use of teicoplanin, because of economic incentives and reservations about its clinical efficacy and potential impact on resistance.1417 This programme was well accepted, as shown by the fact that only two of 61 glycopeptide courses included teicoplanin, and the observation that, of the four antimicrobial agents studied, these drugs achieved the highest (93%) rate of appropriate prescribing. Compared with vancomycin, imipenem and piperacillin–tazobactam were less well prescribed, although more than three-quarters of prescriptions were eventually found to be appropriate.

In contrast, the majority of ciprofloxacin prescriptions were found to be inappropriate. Fluoroquinolones are now widely used both in hospitals and the community because of their broad spectrum of activity, favourable pharmacokinetic profile and availability of an oral formulation, all probably contributing to the high, and potentially excessive, use of these drugs. The potential misuse and increasing resistance to quinolones is, however, of growing concern.1825 Our guidelines therefore recommended conservative use of ciprofloxacin. Despite a marked reduction of ciprofloxacin use during the second survey, the majority of indications and/or route of administration still did not conform to guidelines. Most inadequate orders were associated with therapy of community-acquired infections, where narrower-spectrum drugs could have been used. Antibiotic counselling resulted in 12 (86%) of 14 evaluable prescriptions being eventually appropriate, a marked improvement over the rate recorded in the previous survey. Auditing and monitoring the use of drugs such as fluoroquinolones appears to be important. Whether other much-used drugs such as cephalosporins also need particular attention and regulation need further evaluation.

Improving appropriateness of therapy at the time of initial empirical prescribing is a difficult challenge associated with many organizational constraints and manpower requirements.11 Where available, computer-assisted prescribing may help to guide physicians,26,27 but more than one-third of such recommendations may not be followed by prescribers.27 Our results confirm the tendency of physicians to prescribe unduly broad-spectrum therapy empirically. However, many of the therapeutic courses audited were prescribed for therapy of severe infections (Table IGo). In this context, many initially empirical therapy courses are documented subsequently: we found that about three-quarters of initially empirical prescriptions were eventually documented microbiologically. It is, therefore, especially important that therapy be re-evaluated and, if necessary, adapted 3–4 days after initiation of therapy. Direct liaison with prescribers and counselling at this stage appears to be essential and is more likely to result in better adequacy of therapy than at an earlier stage.

As has been reported previously,22 our study shows that implementation of an antibiotic order form for restricted antibiotics and follow-up by pharmacists can be associated with a marked reduction in antibiotic consumption and with acceptably appropriate use of some of the drugs under restricted use. Substantial misuse may persist for some other drugs that may be difficult to control only through restricted access and controlled delivery. Auditing antibiotic usage and reinforcing practice guidelines through direct counselling thus appears to be warranted. Surveillance programmes may be focused on high-risk areas such as intensive care units, as suggested by Archibald et al.28 Specific classes of drugs, especially those that are easily and largely used empirically, such as fluoroquinolones, may also be at particularly high risk of misuse,29,30 and could be targeted in control programmes, as illustrated by our results. A combination of both restrictive and educational measures appears to be necessary to improve overall antibiotic usage in hospitals.11,31,32 This multifaceted approach should involve pharmacists, clinical microbiologists and infectious diseases experts.

Appendix:



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Appendix Appendix: Order form used for the 23 restricted antibiotics

 
Notes

* Corresponding author. Unité d'Hygiène et Prévention de l'Infection et Service de Réanimation Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, 51 Avenue Maréchal de Lattre de Tassigny, 94010 Créteil, France. Tel: +33-1-4981-2394; Fax: +33-1-4207-9943; E-mail: christian.brun-buisson{at}hmn.ap-hop-paris.fr Back

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Received 10 December 1999; returned 13 March 2000; revised 6 April 2000; accepted 3 May 2000





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