Antimicrobial Use at a University Hospital: Appropriate, Misused Or Abused

Pharmacoepidemiology and Drug Safety Original report

Antimicrobial use at a university hospital: appropriate or misused? A qualitative study

Vera Vlahović-Palčevski, MD, PhD1; Igor Francetić, MD, PhD2; Goran Palčevski, MD, PhD3; Srđan Novak, MD, PhD4; Maja Abram, MD, PhD5 Ulf Bergman, MD, PhD6 1 Department for Clinical Pharmacology, University Hospital Center Rijeka, University of Rijeka Medical School, Rijeka, Croatia 2 Unit for Clinical Pharmacology, Department of Medicine, University Hospital Center Rebro, Zagreb, University of Zagreb Medical School, Croatia

3 Pediatric Clinic, University Hospital Center Rijeka, Croatia

4 Department of Medicine, University Hospital Center Rijeka, University of Rijeka Medical School, Croatia

5 Department for Clinical Microbiology, University Hospital Center Rijeka, University of Rijeka Medical School, Croatia

6 Division of Clinical Pharmacology, Department of Laboratory Medicine, WHO Collaboration Centre for Drug Utilisation Research and Clinical Pharmacological Services, Karolinska Institute, Karolinska University Hospital- Huddinge, Stockholm, Sweden

Acknowledgments: This work was supported by a grant from the Ministry of Science and Technology, Croatia (Grant No 0069062). We acknowledge the Swedish Institute for a scholarship and Pharmacia Corp. for an unrestricted grant to Vera Vlahović- Palčevski. We also thank Paolo Bajčić, MD, for his assistance in data collection.

Corresponding author: Vera Vlahović-Palčevski, MD, PhD Department of Clinical Pharmacology University Hospital Center Rijeka Krešimirova 42 51000 Rijeka Croatia Email: [email protected] Telephone: +385 51 658 805 Fax: + 385 51 658 826 Short title: The quality of antimicrobial use in hospital

Key words: antimicrobial use, quality, hospital, Kunin’s quality criteria

Abstract Objective: To evaluate the quality of antimicrobial drug use at the Department of

Medicine with 270 patient beds at the University Hospital Rijeka, Croatia.

Methods: The appropriateness of antimicrobial treatment was assessed in a prospective, longitudinal survey, during a 21-week period using modified Kunin’s criteria. Criteria were categorized as follows:

I. Agree with the use of antimicrobial therapy, the protocol is appropriate; II. Agree with the use of antimicrobial therapy, the protocol is probably appropriate; III. Agree with the use of antimicrobial therapy, but a different antimicrobial is preferred;

IV. Agree with the use of antimicrobial therapy but a different mode of use is preferred; and V. Disagree with the use of antimicrobial therapy, administration is unjustified.

Categories I. and II. indicate “appropriate therapy”, categories III. and IV. indicate some major deficiency in the choice or use of antimicrobials.

Results: During the study period 438 patients were treated with antimicrobials at the

Department of Medicine. Of these, 159 (36%) had received antimicrobials appropriately (category I and II), 180 (41%) needed antimicrobials (category III and

IV) but they should have been prescribed differently. The main reason for inapproprite antimicrobial treatment was the wrong choice of animicrobials (broad-spectrum where a narrow spectrum would suffice). Ninty-nine patients (23%) did not need antimicrobials at all (category V).

Conclusion: The main reason for suboptimal use of antimicrobials was over- prescribing of broad-spectrum antimicrobials, and its reduction should be a major goal of the stewardship program in the Department of medicine in our institution.

Key points:  Appropriate antimicrobial drug use is the one that maximizes therapeutic impact

while minimizing toxicity and development of resistance. It means prescribing

an antimicrobial only when it is beneficial to the patient, targeting therapy to the

likely or defined pathogen and using adequete drug, in optimal dose, duration

and intervals.

 Before prescribing an antimicrobial a physician should answer these questions:

- Is antimicrobial treatment really necessary?

- Which antimicrobial is the most suitable for the patient?

- How to use it (route, dose, interval and duration)?

 Kunin’s criteria for the evaluation of the appropriateness of antimicrobial

treatment represent a simple quality assessment method that covers almost all

aspects of antimicrobial therapy.

 Hospital antimicrobial stewardship program should be based on local qualitative

assessment of antimicrobial drug use including data on resistance patterns.

Introduction

Many surveys during the past decades have demonstrated that more than half of antimicrobial use in hospitals is inappropriate (1-7). The major issue in promoting rational antimicrobial use is the growing concern about antimicrobial resistance and patient safety. Appropriate antimicrobial drug use is defined as the use that maximizes therapeutic impact while minimizing toxicity and development of resistance. It means prescribing an antimicrobial only when it is beneficial to the patient, targeting therapy to the desired pathogen, and using the appropriate drug, in optimal dose and duration.

We have previously reported on the results of a survey assessing the necessity of antimicrobial drug prescribing at the Department of Medicine at the University Hospital

Rijeka by using a point scoring system as a key quality indicator (5). We found that as much as one third of all antimicrobials were prescribed to patients without clear indications. As a sequele to that we now report on the quality of antimicrobial drug prescribing by assesing the appropriateness of its use in the same study population.

Methods

Setting

The University Hospital Centre Rijeka is an 1191-patient-bed teaching hospital in

Croatia comprised of departments covering all major specialities. The Department of

Medicine had 279 hospital-beds with wards representing endocrinology, gastroenterology, hematology, clinical immunology, cardiology and coronary care unit, nephrology and pulmonology (5).

Study design

We prospectively examined the appropriateness of antimicrobial treatment of adult in- patients at the Department of Medicine, for whom new antimicrobials were prescribed during a 21-week period, between January 17th and June 13th 2003.

The medical records of all hospitalized patients were reviewed daily during the survey period. The diagnosis and relevant clinical data of each patient receiving an antimicrobial were recorded into a patient-specific form. The substance prescribed, the duration of treatment, the dosage, the route and interval of antimicrobial administration were also recorded. Prophylactic use of antimicrobials was not evaluated. The data were analysed by specialists in Internal Medicine, Clinical Pharmacology and Clinical

Microbiology (5).

The appropriateness of antimicrobial treatment was evaluated by using modified

Kunin’s criteria (6).

The following categories were used:

I. Agree with the use of antimicrobial therapy, the protocol (choice, route, duration, and dosage) is appropriate.

II. Agree with the use of antimicrobial therapy, the protocol (choice, route, duration, and dosage) is probably appropriate. Usually a microbiology report is missing to classify the protocol in another category.

III. Agree with the use of antimicrobial therapy, but a different antimicrobial (less expensive, less toxic, narrower spectrum, other combination) is preferred.

IV. Agree with the use of antimicrobial therapy but a modified dose, interval, duration or route of administration is preferred.

V. Disagree with the use of antimicrobial therapy, administration is unjustified.

Categories I. and II. indicate “appropriate therapy”, categories III. and IV. indicate that there was some major deficiency in the choice or use of antimicrobials (6). Category V. indicates unnecessary antimicrobial use and corresponds to the score less than 3 according to the scoring system presented in our earlier study (5).

These Kunin´s categories are illustrated by clinical examples in Table 1.

The evaluation and categorization of antimicrobial treatment was carried out upon the agreement between the authors. It was based on the microbiology reports, major published guidelines and recommendations for antimicrobial drug use and the knowledge on local resistance patterns (8-21). Local guidelines on antimicrobial drug use did not exist except for the ruling of restricted release antimicrobial described in the previous study (5).

Statistical evaluation of data was performed using Statistica 6.0. software. The comparisons were made using appropriate statistical tests with the significance level at

Ethical considerations

This survey is a part of quality control of drug utilization, and therefore does not require the Hospital Ethics Committee approval.

Results

During the study period 438 patients were treated with antimicrobial agents at the

Department of Medicine. One hundred fifty-nine (36%) had received antimicrobials appropriately (cat. I. and II), 180 (41%) needed antimicrobials, but prescribed differently with regard to the choice, dosage, route, interval or duration of treatment

(cat. III. and IV.) and 99 (23%) did not need antimicrobials, but had received it (Table

We have not found significant difference in the appropriateness of antimicrobial drug use (expressed as categories I-V) between the wards. The median category in all wards was III (Kruskal-Wallis ANOVA by Ranks; Kruskal-Wallis test: H(6, N=438) =

8,125001 p=0,2291) (Table 2A).

The appropriateness of antimicrobial drug use according to diagnoses showed significant difference, with sepsis being treated most appropriately (Table 2B)

(Kruskal-Wallis ANOVA by Ranks; Kruskal-Wallis test: H (9, N=438) =39,61257

P<0,001). A significant difference was found also in the appropriateness of use of selected substances, with broad spectrum agents being used inappropriately more often than the narrow spectrum (Table 2C.) ( Kruskal-Wallis ANOVA by Ranks; Kruskal-Wallis test:

H (27, N=438) =57,76266 p=0,0005).

Discussion

Strategies to prevent and control emergence and spread of antibiotic-resistant pathogens in hospitals are based mainly on effective infection control and prevention measures and antimicrobial stewardship programs. It has been shown that despite these efforts, nearly one third of antimicrobials prescribed for hospitalized patients are not necessary

(5,7).

In this study we have addressed the question of the quality (appropriateness) of antimicrobial drug use for hospitalized patients.

We used modified Kunin’s criteria because the method is simple and covers almost all aspects of antimicrobial therapy (8).

We tried to find out the proportion of patients receiving antimicrobials inappropriately, and the most probable reason for it. The hypothesis was that if these drugs were not used appropriately in some wards more often than in others, the most probable reason would be local prescribing habits, policy or management. If certain illnesses were not treated appropriately, the most probable reason would be lack of treatment guidelines, and finally if a certain antimicrobial was misused more often than the others, in addition to the lack of guidelines, possible reasons could be diagnostic uncertainty and industry pressure. Each of these deviations should be approached differently!

Forty-one percent of the patients treated with antimicrobials should have received them differently, but their distribution according to different wards was similar, meaning that a single ward was not responsible for the antibiotic misuse. The main reason for inappropriate antimicrobial treatment was the wrong choice of antimicrobials (Kunin’s cat. III). One half of the patients were prescribed antimicrobials for respiratory tract infections, of which 42% inappropriately (the wrong choice). Also, more than half of the patients treated for abdominal and skin and soft tissue infections were not treated correctly for the same reason. Improving adherence to major published guidelines for antimicrobial treatment, or publishing local ones would be the most effective means to reduce this type of misuse. In addition, a feedback program to prescribing clinicians, as a part of quality circle has been accepted as a simple intervention on prescribing behavior. The feedback summary may also include recommendations for clinical action

Aminoglycosides and vancomycin were given to more than 2/3 of the patients when they should not have been used. As these are old drugs, and have narrow spectrum, pharmaceutical pressure probably did not play a major role in their misuse. We assume that it is due to diagnostic uncertainty, and prescribing by inexperienced physicians.

Therapeutic guidelines and educational efforts should be strongly encouraged to improve this.

Mostly misused broad-spectrum agents were 3rd and 4th generation cephalosporins and co-amoxiclav. Physicians often opt for broad-spectrum antibiotics because of diagnostic uncertainty, but the role of pharmaceutical industry should not be neglected, as these newer agents are costly.

Our findings suggest that the main reason for suboptimal use of antimicrobials was over-reliance on broad-spectrum antimicrobials, and its reduction should be a major goal of the stewardship program in our institution. Appropriate antimicrobial stewardship that includes optimal selection, dose and duration of treatment, as well as control of antimicrobial drug use, will prevent or slow the emergence of resistance among microorganisms. In addition, optimizing antimicrobial use may reduce pharmacy expenditures.

Further work is required to define the most efficient means to improve hospital antimicrobial drug use.

Based on the results of this study, local guidelines for antimicrobial drug use will be developed as well as measures to promote their implementation.

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Table 1. Examples of clinical scenarios in each category of appropriateness of antimicrobial treatment

Antimicrobial therapy is:

- appropriate (Category I) An 82-year old woman was admitted with fever 38,2ºC, chills, malaise and back pain, which started three days before admission. The examination showed a systolic aortic murmur, sedimentation rate 53 mm/hour and leukocytosis 11.000/mm3. Urine and blood cultures were taken and antimicrobial treatment was started (benzylpenicillin 2 MIU every 4 hours plus gentamycin 160mg once daily). Urine culture was negative. Blood culture confirmed the suspected Streptococcus viridans endocarditis. - probably appropriate (Category II). A 69-year old woman with ischemic heart disease was admitted from home with signs and symptoms of pneumonia, which was confirmed radiografically. Microbiology testing was not performed. The presumed pathogen was Haemophilus influenzae. She was treated with cefuroxime, 750 mg every 8 hours intravenously for six days. As the symptoms subsided, the regimen was switched to oral, 500 mg every 12 hours for another 7 days. Comment: Microbiology testing was not performed to confirm diagnose. Clinical improvement speaks in favor of correct empiric treatment.

- agree with the use ofantimicrobial, but a different agent is suggested/preferred (Category III). A 35-year old woman was admitted with signs and symptoms of community acquired pneumonia. She was prescribed empirically a combination of co-amoxiclav intravenously 1,2 g every 8 hours and doxycycline orally 100 mg daily, for 10 days. The symptoms persisted and the therapy was switched to ciprofloxacin intravenously 500 mg every 12 hours for 21 day. On the 12th day of ciprofloxacin therapy, oral clarythromycin, 250mg every 12 hours was added to the regimen. Comment: The most common pathogens in community-acquired pneumonia in young adults are Streptococcus pneumoniae or Mycoplasma pneumoniae and less likely H. influenzae and Legionella spp. An example of adequate empiric treatment would be azithromycin (good coverage of likely atypical pathogens or pneumococci and H. influenzae), or a floroquinolone. In addition penicillin and a tetracycline should not be given simultaneously because of their antagonistic activity.

- agree with the use of antimicrobial, but a modified dose, interval, duration or route of administration is suggested/preferred (Category IV) A 70-year old woman with a history of ischemic heart disease and normal renal function was admitted to regular ward with signs and symptoms of lower respiratory tract infection (acute exacerbation of chronic bronchitis). She was treated empirically with amoxicillin 500 mg orally, once daily for 22 days. Comment: amoxicillin should be given 3 times daily

- unnecessary (Category V) A 59-year old man was admitted due to gastrointestinal bleeding (duodenal peptic ulcer). Two hours after a single blood transfusion he got chills and his body temperature rose to 38,1ºC. He was otherwise asymptomatic, with no evidence of infection but was treated empirically with co-amoxiclav for 7 days. Comment: the transfusion, not an infection, caused the fever reaction.

Appropriate % Inappropriate % Unnecessary Therapy (36) Therapy (41) Treatment I II III IV V % Total (57) (102) (162) (18) (99) (23) (438) A Ward Cardiology 13 14 41 15 4 29 20 30 66 Endocrinology 10 4 48 9 2 38 4 14 29 Gastroenterology 11 13 25 44 1 47 26 27 95 Hematology 1 5 27 10 45 6 27 22 Immunology 1 4 31 8 1 56 2 13 16 Nephrology 9 8 35 13 10 47 9 18 49 Pulmonology 12 54 41 63 39 32 20 161 B Diagnosis Abdominal infection 9 11 39 32 42 25 32 77 Endocarditis 1 33 2 67 3 Malignancy 8 62 5 25 7 35 20 Pericarditis 1 1 RTI 19 55 46 81 7 42 49 23 211 Sepsis 2 2 100 4 Skin and soft 3 5 35 11 4 52 6 21 29 tissue infection Tuberculosis 1 5 50 6 43 2 14 14 Unclear 1 1 25 6 75 8 UTI 22 16 57 23 6 41 4 6 71 C Antimicrobial Aminopenicillins 10 5 44 7 5 35 7 21 34 Antituberculotics 7 7 Aminoglycosides 1 4 18 17 1 64 5 18 28 1st and 2nd generation cephalosporins 21 26 51 19 4 25 23 25 93 3rd and 4th generation cephalosporins 3 7 25 23 1 60 6 15 40 Co-amoxiclav 2 16 15 64 5 58 31 26 118 Macrolides 5 36 6 43 3 21 14 Penicillin 1 1 2 Tetracyclines 9 47 1 5 9 47 19 Quinolones 16 19 52 17 2 28 13 19 67 Vancomycin 1 1 29 4 57 1 14 7 Other 2 3 56 3 33 1 11 9

Table 2 A-C. Appropriateness of antimicrobial treatment in different wards, in different indications and by selected substances. (Cat. I. Agree with the use of antimicrobial therapy, the protocol (choice, route, duration, and dosage) is appropriate. Cat. II. Agree with the use of antimicrobial therapy, the protocol (choice, route, duration, and dosage) is probably appropriate. Cat. III. Agree with the use of antimicrobial therapy, but a different antimicrobial (less expensive, less toxic, narrower spectrum, other combination) is preferred. Cat. IV. Agree with the use of antimicrobial therapy but a modified dose, interval, duration or route of administration is preferred. Cat.V. Disagree with the use of antimicrobial therapy, administration is unjustified.).