- Email: [email protected]
Impact of an antimicrobial formulary and restriction policy in the largest hospital in Italy
International Journal of Antimicrobial Agents 16 (2000) 295 – 299 www.ischemo.org
Impact of an antimicrobial formulary and restriction policy in the largest hospital in Italy M. Bassetti a,*, A. Di Biagio a, B. Rebesco b, G. Cenderello a, M.E. Amalfitano b, D. Bassetti a a
Department of Infectious Disease, Uni6ersity of Genoa, San Martino Hospital, L.go R. Benzi 10, 16132 Geno6a, Italy b Department of Pharmacy, San Martino Hospital, Genoa, Italy Accepted 27 July 2000
Abstract We have analysed the expenditure on antimicrobial drugs in the largest hospital in Italy; over this period, a committee prepared an antibiotic policy document. This formulary lists all antimicrobial drugs available in the hospital. Some drugs were removed from the list and others are only available on special request for a named patient. In the hope of optimising drug utilisation, we included all the reasons for the choice of agent in the document. The introduction of this formulary resulted in an immediate saving and perhaps in the future we shall also observe an improvement in bacterial resistance patterns. © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Antimicrobial cost; Drugs budget; Antibiotic use
1. Introduction The use of antimicrobial agents in developed countries is reported to be inappropriate in 20 – 60% of cases. This may result through incorrect pharmacological choice (e.g. use of broad-spectrum antibiotics when unnecessary, use of antibacterial drugs as antipyretics, etc.) but chiefly occurs because of inappropriate dosage and irrational treatment length. Antibiotics comprise a wide range of drugs with \ 200 substances approved and thus, available for clinical use. Some antibiotics occur very frequently in medical prescriptions, particularly in the hospital environment, while other drugs with the same or greater efficacy and often lower cost, are ignored. New agents that have optimum microbiological and pharmacological features should be administered in only a few selected and targeted cases. It is difficult for physicians to keep up to date on new substances and the latest antimicrobial resistance patterns. * Corresponding author. Tel.: +39-010-5552668; fax: + 39-0105556712. E-mail address: [email protected] (M. Bassetti).
The extensive use of antibacterial agents is paralleled by the growing frequency of multidrug resistant strains (MDR) which is said to be related to the overuse of antibiotics, both in prophylaxis and in therapy [1–4]. The last 15 years have seen the growth of MDR-bacteria such as Staphylococcus aureus met-R, vancomycinresistant enterococci (VREF) and resistant Gram-negative bacteria (Pseudomonas spp., Escherichia coli, Klebsiella spp., Serratia spp., Enterobacter spp.) [5]. New classes of antibiotics may not be available in the future, therefore we should design, formulate and carry out a policy that establishes the best use of drugs which are now available [6–9]. As a group of drugs, antibiotics have the greatest impact on the hospital budget, being : 25% of the total drug expenditure. Such cost must be limited, however, this should be done not just considering economical aims, but after a proper analysis of each drug. In order to optimise the use of antimicrobial agents, we need to know the local management of antibiotic therapy and the microbiology of the local bacterial strains. Both the use of these drugs and the incidence of bacterial resistance vary in different hospitals.
0924-8579/00/$ - $20 © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 0 ) 0 0 2 4 9 - 1
M. Bassetti et al. / International Journal of Antimicrobial Agents 16 (2000) 295–299
296
The hospital pharmacist — who is responsible for checking prescriptions — should therefore work together with the infectious disease specialist, who is the main consultant concerned with anti-infective therapy. Since the beginning of the 1980s, policies for the reduction of antibiotic use and related costs have been established in the US and northern Europe [10–12]. Nowadays almost all American hospitals have a committee that controls drug spending, especially for antimicrobial agents [13,14]. In our hospital, after analysing prescriptions for 3 years, we have tried to rationalise the use of antibiotics through a policy of accurate information and if needed, restrictions of use modelled on data from other countries.
We have observed that the most commonly used antibiotics were the third generations cephalosporins costing 1.4 million Euros per year, i.e. : 40% of the total chemotherapy budget. Ceftazidime was most frequently administered with a cost of 723 000 Euros per year, followed by ceftriaxone 387 000 Euros per year. We looked at departments using larger quantities of these drugs for specific purposes. Ceftazidime was prescribed as perioperative prophylaxis in surgery. Carbapenems were used more in surgery and internal medicine than in the ICU or haemato/oncology. Detailed analysis of other classes of antibiotics showed other prescription variation. The trend of bacterial resistance in the hospital showed a continuous high level of resistance in both Gram-positive and Gram-negative species.
2. Background
3. Materials and methods
S. Martino teaching hospital with 2500 beds is the largest hospital in Italy and one of the largest in Europe. We analysed the use and the cost of antibiotics from 1995 to 1997 for each department in this hospital, after dividing the hospital into four large sections: surgery (S), internal medicine (IM), intensive care unit (ICU) and haemato/oncology (HO). In S. Martino the cost of antimicrobials was 26% of total drug expenditure during the period examined. The cost per year of antibiotics was :3.25 million Euros; other drugs cost :8 million Euros per year. Even though the total expense did not change over the period we looked at, the number of admission and hospitalisation length sharply decreased and there was a constant increase of antibiotics cost from 4.05 Euros daily in 1995 to 4.51 Euros daily in 1997. The average expenditure was 12% for antimicrobials agents but 36% for other drugs (from 1.12 Euros in 1995 to 15.17 Euros in 1997) (Table 1).
After a complete evaluation of all data, the Therapeutic Committee for Hospital Formulary (TCHF) of SMTH decided to create a formulary of antimicrobials agents which would contain all decisions taken by the Committee. As a result of the analysis, a committee composed of the head of the pharmacy department, infectious disease specialists, a pharmacologist expert and a medical executive of the hospital decided to exclude some drugs from the formulary and to allow the use of other drugs only on a specific named patient demand. Such decisions were made on the basis of the real cost/benefit and cost/effectiveness ratio of each compound, including consideration of the selective pressure on some antibacterial drugs. Sequential therapy was one of the most important concepts used in compiling the formulary with a preference for drugs available both in parenteral and oral formulations [15]. In sequential therapy, the substance should be the same and can optimise cost by an earlier discharge of the patient from hospital.
Table 1 Admissions, drug costs and antimicrobial costsa 1995 No. ordinary admissions No. day hospital admissions Total no. admissions Total no. days of hospitalisation Average no. days of hospitalisation Cost of all drugs Cost of drugs other than antimicrobials Cost of antimicrobials Cost of drugs for each admission Cost of drugs other than antimicrobials per day Cost of antimicrobial drug per day of hospitalisation a
All costs are in Euros.
57 797 28 169 85 966 809 818 12.7 11 435 388 8 159 502 3 275 886 133.02 11.12 4.07
1996 58 316 25 830 84 146 789 419 11.9 11 944 015 8 610 885 3 333 729 141.95 12.39 4.22
1997 57 371 25 101 82 472 727 641 11.0 12 814 845 9 512 619 3 297 060 154.94 15.17 4.53
1998 56 607 27 147 83 754 707 820 10.7 12 840 667 9 886 534 2 954 133 153.31 16.35 4.17
M. Bassetti et al. / International Journal of Antimicrobial Agents 16 (2000) 295–299
All decisions were included in a formulary published as a handbook and sent to the medical staff and nurse supervisor responsible for each department. In this handbook, all the compounds were classified as an anatomic, therapeutic, chemical scheme (ATC) [16] and the formulations available were included as well as the dosage, route of administration, pharmacodynamic and pharmacokinetic notes and spectrum of action. The TCHF included the reasons for the choice of one antibiotic instead one of another of the same family. We designated the therapeutic indications, average dosage, daily defined dose (DDD) and cost of DDD of each antibiotic [17]. There are 31 antibiotics without restricted use, they are: doxycycline, amoxycillin, chloramphenicol, penicillin G, ampicillin, mezlocillin, coamoxyclavulanate, sulbactam ampicillin (only for i.m. use), cefazolin, cefotetan, cefotaxime, ceftizoxime, ceftriaxone, cefaclor, trimethoprim/sulphamethoxazole, clarithromyicin, erythromycin, spiramycin, clindamycin (only for i.v. use), amikacin, gentamicin, streptomycin, pipemidic acid, ciprofloxacin, pefloxacin, teicoplanin, vancomycin, colistin, metronidazole and fosfomycin. Tazobactam/piperacillin, ceftazidime, cefepime and meropenem are included only on a named patient drug demand sheet, which should be certified by an infectious disease consultant or supported by microbiological data including susceptibility tests. Then, in the second part of the handbook TCHF included 22 antibiotics erased with the reasons for this decision; these are listed in Table 2. The decisions came in force from January 1, 1998. After 14 months we evaluated the cost of antibiotics and other drugs between 1998 and the previous period. The costs (measured in Euro) and the cost of DDD did not increase during the period of observation. The consumption of antibiotics were evaluated using the international measure, DDD which is the medium dose of determined drug for an adult patient referring to main therapeutic function (or aim). In this paper the consumption of drugs in DDD× 100 patients per day is used [16,17].
4. Results From the cost analysis we found that with a similar number of days of hospitalisation (727 641 days in 1997 versus 707 280 days in 1998), the cost of antibiotic drugs decreased in 1998 after the introduction of the formulary by 10.5% with a saving of 345 000 Euros. The average cost of antibiotic per day of hospitalisation decreased from 4.53 Euros in 1997 to 4.18 Euros in 1998 with a saving of 8.5% in 1 year. The most dramatic reduction seen was for ceftazidime, available only
297
Table 2 Antimicrobial drugs withdrawn and reasons for this Antibiotic withdrawn
Reason
Minocycline
Similar to doxycycline but more expensive Very expensive Unsuitable route of administration
Thiamphenicol vls. Thiamphenicol.vls. for aerosol Oral ampicillin Bacampicillin Piperacillin Benzathine penicillin + benzylpenicillin Sulbactam/ampicillin
Less bioavailability than amoxycillin Same molecule as ampicillin Cost/benefit unfavourable; use a ureidopenicillin such as mezlocillin Procaine may be harmful so penicillin alone or benzathine benzylpenicillin would be better
Cost/benefit unfavourable; not available for sequential therapy Clavulanic acid/ticarcillin Cost/benefit unfavourable; not available for sequential therapy Cefuroxime axetil Low bioavailability Cefoperazone Cost/benefit unfavourable Cephalothin Requires from 4 to 6 dose per day; cannot be used with aminoglycosides, frusamide or polymyxin in kidney failure Cefodizime Cost/benefit unfavourable, not shown in vitro pro-host effect Aztreonam Cost/ benefit unfavourable, compared with other aminoglycosides that have a similar spectrum Roxithromycin Older than other macrolides Lincomycin More restricted spectrum and activity than clindamycin Oral clindamycin Greater risk for C. difficile related colitis Netilmicin Cost/benefit unfavourable compared with gentamicin. or amikacin Tobramycin Cost/benefit unfavourable compared with gentamicin Norfloxacin Better to use earlier fluoroquinolones in UTI Ofloxacin Cost/benefit unfavourable compared with ciprofloxacin Oral pefloxacin Cost/benefit unfavourable compared with ciprofloxacin
on special named patient request, whose cost decreased by 52% from 741 000 Euros in 1997 to 356 000 Euros in 1998 (Table 3). This reduction was chiefly due to the use of ceftazidime only in cases when it was specifically needed; in all other cases lower cost alternative were used. Expenditure on tazobactam/piperacillin, another restricted drug, was reduced by 26%; previously due to activity against anaerobic bacteria, it had mainly been used for prophylaxis (Table 3). Imipenem was removed because of significant resistance problems in Gram-negative bacteria. Meropenem was restricted, but the expenditure was similar to that before because carbapenems were administered as sug-
M. Bassetti et al. / International Journal of Antimicrobial Agents 16 (2000) 295–299
298
Table 3 Cost (×1000) of the main antibiotics used 1996–1998 1996 Tazo-piperacillin Meropenem Ceftazidime Ceftriaxone Ceftizoxime Cefotaxime Cefazolin Vancomycin Teicoplanin Amoxy/clav Mezlocillin Ciprofloxacin Aztreonam Imipenem Piperacillin Other antibiotics Total
1997
prophylaxis increased from 1996 to 1998 to 348 and 220%, respectively. 1998
59 879 140 129 702 838 387 902 120 616 106 442 20 217 244 228 311 357 10 087 290 57 135 60 503 279 936 262 631 538 881
189 706 148 209 741 418 373 388 173 902 107 204 19 016 223 056 292 318 22 382 1 074 86 989 81 094 207 790 184 965 433 645
139 489 168 020 355 070 439 675 292 896 213 023 40 606 184 761 375 712 40 878 34 818 12 820 30 890 48 966 0 469 226
3 275 887
3 302 764
2 954 415
gested by TCHF for the ICU and uncomplicated postsurgery infections instead of for surgical prophylaxis or for mild infections. Teicoplanin costs increased by 28% mainly in surgery, but this drug was used only in serious infections due to Gram-positive, resistant bacteria [18]. The DDD values per 100 patients per year are shown in Table 4. Ceftriaxone was the most prescribed drug in SMTH during 1998 and it was used in 4.9 patients each day for 100 patients. Third generation cephalosporins are still the most commonly prescribed drugs in SMTH, as we noticed in previous reports. The use of amoxycillin/clavulanic acid and ceftizoxime most commonly used for sequential therapy of severe infections and the second choice for surgical Table 4 Daily defined dose for 100 hundred patients per day 1996 Tazo/piperacillin Meropenem Ceftazidime Ceftriaxone Ceftizoxime Cefotaxime Cefazolin Vancomycin Teicoplanin Clavulanic acid amoxycillin Mezlocillin Ciprofloxacin Aztreonam Imipenem Piperacillin
0.043 0.41 2.6 4.21 1.2 0.78 0.67 1.1 1.35 0.5 0.004 0.2 0.28 1 1.6
1997 0.142 0.56 3 4.06 1.84 0.85 0.42 1.1 1.34 1.18 0.014 0.32 0.27 0.8 1.25
1998 0.108 0.58 1.33 4.9 3.17 1.68 1.1 1.01 1.73 2.24 0.5 0.45 0.14 0.18 0
5. Conclusions About 500 of named patient requests were made after January 1, 1998, which were evaluated by an infectious disease consultant. There was an initial difficult period when physicians working in SMTH had to acclimatise to the new strategies and rules for antibiotic therapy, but these problems are now resolved. This exercise reduced the use of some antibiotics which were not used properly [19]; the restriction policy has resulted in clear and immediate saving and we hope for an improvement in the future in the bacterial resistance pattern induced by the reduced selective pressure on the same pathogens. Some antibiotics that were less frequently administrated are now correctly used and have replaced others. This improvement in antibiotic choice has resulted in a considerable saving and hopefully a better resistance pattern for the future. Some physicians queried some aspects of this formulary and their observations have helped mould the present policies. The formulary is constantly updated on the basis of microbiological resistance changes and of changes in use of antibiotics. On the basis of the early results of this policy, we suggest this policy could help many other drug categories which are equally expensive and badly used. We hope to optimise the drug use in the future without a restriction policy, but by the provision of improved information for the user.
References [1] Frank MO, Batteiger BE, Sorensen SJ, et al. Decrease in expenditure and selected nosocomial infection following implementation of an antimicrobial- prescribing improvement program. Clin Perform Qual Health Care 1997;5:180 – 8. [2] Jarvis WR. Preventing the emergence of multi-drug microorganisms through antimicrobials use controls: the complexity of the problem. Infect Control Hosp Epidemiol 1996;17:490 –5. [3] McGowan JE. Do intensive hospital antibiotic control programs prevent the spread of antibiotic resistance? Infect Control Hosp Epidem 1994;15:478 – 83. [4] Rahal JJ, Urban C, Horn D, et al. Class restriction of cephalosporins use to control total cephalosporins resistance in nosocomial Klebsiella. J Am Med Assoc 1998;14:1233 –7. [5] Neu HC. The crisis in antibiotic resistance. Science 1992;257:1064– 73. [6] Bryan CS. The role of infectious disease physician in setting guidelines for antimicrobials use. Bull NY Acad Med 1987;63:627 – 37. [7] John JF, Fishman NO. Programmatic role of the infectious diseases physician in controlling antimicrobial costs in the hospital. Clin Infect Dis 1997;24(3):471– 85.
M. Bassetti et al. / International Journal of Antimicrobial Agents 16 (2000) 295–299 [8] Marr JJ, Moffet H, Kunin CM. Guidelines for improving the use of antimicrobial agents in hospitals: a statement by the Infectious Disease Society of America. J Infect Dis 1998;157:869 – 76. [9] Gross PA. Practice guidelines for infectious disease: a rational for a work in progress. Clin Inf Dis 1998;26:1037–41. [10] Coleman RW, Rodondi LC, Keubisch S, et al. Cost-effectiveness of prospective and continuous parenteral antibiotic control: experience at the Palo alto Veterans Affairs Medical Center from 1987 to 1989. Am J Med 90;1991:439–44. [11] Molly T, Shalini G, Moses BV, Abraham J. Monitoring of antibiotic use in a primary and tertiary care hospital. J Clin Epidemiol 1996;49(2):251–4. [12] Eherenkranz NJ. Containing costs of antimicrobials in the hospital: a critical evaluation. Am J Infect Control 1989;17(5):300– 10. [13] Karki SD, Holden JM, Mariano E. A team approach to reduce antibiotic costs. DICP Ann Pharmacother 1990;24:202–5.
.
299
[14] Woodward RS, Medoff G, Smith MD, et al. Antibiotic cost savings from formulary restrictions and physician monitoring in a medical-school affiliated hospital. Am J Med 1987;83:817–23. [15] MacGowan AP, Bowker KE. Sequential antimicrobial therapy: pharmacokinetic and pharmacodynamic considerations in sequential therapy. J Infect 1998;37(1):30 – 6. [16] WHO. Anatomical Therapeutical Chemical (ATC) Classification Index including Defined Daily Doses (DDDs). WHO Collaborating Center for Drug Statistics Methodology, Oslo, 1995. [17] Clark KW, Gray D. The defined daily dose as a tool in pharmacoeconomics. Advantages and limitation. Pharmacoeconomics 1995;7(4):280 – 3. [18] Morgan AS, Brennan PJ, Fishman NO. Impact of vancomycin restriction policy on use and cost of vancomycin and incidence of vancomycin resistant Enterococcus. Ann Pharmacother 1997;31(9):970– 3. [19] Gould IM, Jappy B. Trends in hospital antibiotic prescribing after introduction of an antibiotic policy. JAC 1996;38:895–904.
Impact of an antimicrobial formulary and restriction policy in the largest hospital in Italy M. Bassetti a,*, A. Di Biagio a, B. Rebesco b, G. Cenderello a, M.E. Amalfitano b, D. Bassetti a a
Department of Infectious Disease, Uni6ersity of Genoa, San Martino Hospital, L.go R. Benzi 10, 16132 Geno6a, Italy b Department of Pharmacy, San Martino Hospital, Genoa, Italy Accepted 27 July 2000
Abstract We have analysed the expenditure on antimicrobial drugs in the largest hospital in Italy; over this period, a committee prepared an antibiotic policy document. This formulary lists all antimicrobial drugs available in the hospital. Some drugs were removed from the list and others are only available on special request for a named patient. In the hope of optimising drug utilisation, we included all the reasons for the choice of agent in the document. The introduction of this formulary resulted in an immediate saving and perhaps in the future we shall also observe an improvement in bacterial resistance patterns. © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Antimicrobial cost; Drugs budget; Antibiotic use
1. Introduction The use of antimicrobial agents in developed countries is reported to be inappropriate in 20 – 60% of cases. This may result through incorrect pharmacological choice (e.g. use of broad-spectrum antibiotics when unnecessary, use of antibacterial drugs as antipyretics, etc.) but chiefly occurs because of inappropriate dosage and irrational treatment length. Antibiotics comprise a wide range of drugs with \ 200 substances approved and thus, available for clinical use. Some antibiotics occur very frequently in medical prescriptions, particularly in the hospital environment, while other drugs with the same or greater efficacy and often lower cost, are ignored. New agents that have optimum microbiological and pharmacological features should be administered in only a few selected and targeted cases. It is difficult for physicians to keep up to date on new substances and the latest antimicrobial resistance patterns. * Corresponding author. Tel.: +39-010-5552668; fax: + 39-0105556712. E-mail address: [email protected] (M. Bassetti).
The extensive use of antibacterial agents is paralleled by the growing frequency of multidrug resistant strains (MDR) which is said to be related to the overuse of antibiotics, both in prophylaxis and in therapy [1–4]. The last 15 years have seen the growth of MDR-bacteria such as Staphylococcus aureus met-R, vancomycinresistant enterococci (VREF) and resistant Gram-negative bacteria (Pseudomonas spp., Escherichia coli, Klebsiella spp., Serratia spp., Enterobacter spp.) [5]. New classes of antibiotics may not be available in the future, therefore we should design, formulate and carry out a policy that establishes the best use of drugs which are now available [6–9]. As a group of drugs, antibiotics have the greatest impact on the hospital budget, being : 25% of the total drug expenditure. Such cost must be limited, however, this should be done not just considering economical aims, but after a proper analysis of each drug. In order to optimise the use of antimicrobial agents, we need to know the local management of antibiotic therapy and the microbiology of the local bacterial strains. Both the use of these drugs and the incidence of bacterial resistance vary in different hospitals.
0924-8579/00/$ - $20 © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 0 ) 0 0 2 4 9 - 1
M. Bassetti et al. / International Journal of Antimicrobial Agents 16 (2000) 295–299
296
The hospital pharmacist — who is responsible for checking prescriptions — should therefore work together with the infectious disease specialist, who is the main consultant concerned with anti-infective therapy. Since the beginning of the 1980s, policies for the reduction of antibiotic use and related costs have been established in the US and northern Europe [10–12]. Nowadays almost all American hospitals have a committee that controls drug spending, especially for antimicrobial agents [13,14]. In our hospital, after analysing prescriptions for 3 years, we have tried to rationalise the use of antibiotics through a policy of accurate information and if needed, restrictions of use modelled on data from other countries.
We have observed that the most commonly used antibiotics were the third generations cephalosporins costing 1.4 million Euros per year, i.e. : 40% of the total chemotherapy budget. Ceftazidime was most frequently administered with a cost of 723 000 Euros per year, followed by ceftriaxone 387 000 Euros per year. We looked at departments using larger quantities of these drugs for specific purposes. Ceftazidime was prescribed as perioperative prophylaxis in surgery. Carbapenems were used more in surgery and internal medicine than in the ICU or haemato/oncology. Detailed analysis of other classes of antibiotics showed other prescription variation. The trend of bacterial resistance in the hospital showed a continuous high level of resistance in both Gram-positive and Gram-negative species.
2. Background
3. Materials and methods
S. Martino teaching hospital with 2500 beds is the largest hospital in Italy and one of the largest in Europe. We analysed the use and the cost of antibiotics from 1995 to 1997 for each department in this hospital, after dividing the hospital into four large sections: surgery (S), internal medicine (IM), intensive care unit (ICU) and haemato/oncology (HO). In S. Martino the cost of antimicrobials was 26% of total drug expenditure during the period examined. The cost per year of antibiotics was :3.25 million Euros; other drugs cost :8 million Euros per year. Even though the total expense did not change over the period we looked at, the number of admission and hospitalisation length sharply decreased and there was a constant increase of antibiotics cost from 4.05 Euros daily in 1995 to 4.51 Euros daily in 1997. The average expenditure was 12% for antimicrobials agents but 36% for other drugs (from 1.12 Euros in 1995 to 15.17 Euros in 1997) (Table 1).
After a complete evaluation of all data, the Therapeutic Committee for Hospital Formulary (TCHF) of SMTH decided to create a formulary of antimicrobials agents which would contain all decisions taken by the Committee. As a result of the analysis, a committee composed of the head of the pharmacy department, infectious disease specialists, a pharmacologist expert and a medical executive of the hospital decided to exclude some drugs from the formulary and to allow the use of other drugs only on a specific named patient demand. Such decisions were made on the basis of the real cost/benefit and cost/effectiveness ratio of each compound, including consideration of the selective pressure on some antibacterial drugs. Sequential therapy was one of the most important concepts used in compiling the formulary with a preference for drugs available both in parenteral and oral formulations [15]. In sequential therapy, the substance should be the same and can optimise cost by an earlier discharge of the patient from hospital.
Table 1 Admissions, drug costs and antimicrobial costsa 1995 No. ordinary admissions No. day hospital admissions Total no. admissions Total no. days of hospitalisation Average no. days of hospitalisation Cost of all drugs Cost of drugs other than antimicrobials Cost of antimicrobials Cost of drugs for each admission Cost of drugs other than antimicrobials per day Cost of antimicrobial drug per day of hospitalisation a
All costs are in Euros.
57 797 28 169 85 966 809 818 12.7 11 435 388 8 159 502 3 275 886 133.02 11.12 4.07
1996 58 316 25 830 84 146 789 419 11.9 11 944 015 8 610 885 3 333 729 141.95 12.39 4.22
1997 57 371 25 101 82 472 727 641 11.0 12 814 845 9 512 619 3 297 060 154.94 15.17 4.53
1998 56 607 27 147 83 754 707 820 10.7 12 840 667 9 886 534 2 954 133 153.31 16.35 4.17
M. Bassetti et al. / International Journal of Antimicrobial Agents 16 (2000) 295–299
All decisions were included in a formulary published as a handbook and sent to the medical staff and nurse supervisor responsible for each department. In this handbook, all the compounds were classified as an anatomic, therapeutic, chemical scheme (ATC) [16] and the formulations available were included as well as the dosage, route of administration, pharmacodynamic and pharmacokinetic notes and spectrum of action. The TCHF included the reasons for the choice of one antibiotic instead one of another of the same family. We designated the therapeutic indications, average dosage, daily defined dose (DDD) and cost of DDD of each antibiotic [17]. There are 31 antibiotics without restricted use, they are: doxycycline, amoxycillin, chloramphenicol, penicillin G, ampicillin, mezlocillin, coamoxyclavulanate, sulbactam ampicillin (only for i.m. use), cefazolin, cefotetan, cefotaxime, ceftizoxime, ceftriaxone, cefaclor, trimethoprim/sulphamethoxazole, clarithromyicin, erythromycin, spiramycin, clindamycin (only for i.v. use), amikacin, gentamicin, streptomycin, pipemidic acid, ciprofloxacin, pefloxacin, teicoplanin, vancomycin, colistin, metronidazole and fosfomycin. Tazobactam/piperacillin, ceftazidime, cefepime and meropenem are included only on a named patient drug demand sheet, which should be certified by an infectious disease consultant or supported by microbiological data including susceptibility tests. Then, in the second part of the handbook TCHF included 22 antibiotics erased with the reasons for this decision; these are listed in Table 2. The decisions came in force from January 1, 1998. After 14 months we evaluated the cost of antibiotics and other drugs between 1998 and the previous period. The costs (measured in Euro) and the cost of DDD did not increase during the period of observation. The consumption of antibiotics were evaluated using the international measure, DDD which is the medium dose of determined drug for an adult patient referring to main therapeutic function (or aim). In this paper the consumption of drugs in DDD× 100 patients per day is used [16,17].
4. Results From the cost analysis we found that with a similar number of days of hospitalisation (727 641 days in 1997 versus 707 280 days in 1998), the cost of antibiotic drugs decreased in 1998 after the introduction of the formulary by 10.5% with a saving of 345 000 Euros. The average cost of antibiotic per day of hospitalisation decreased from 4.53 Euros in 1997 to 4.18 Euros in 1998 with a saving of 8.5% in 1 year. The most dramatic reduction seen was for ceftazidime, available only
297
Table 2 Antimicrobial drugs withdrawn and reasons for this Antibiotic withdrawn
Reason
Minocycline
Similar to doxycycline but more expensive Very expensive Unsuitable route of administration
Thiamphenicol vls. Thiamphenicol.vls. for aerosol Oral ampicillin Bacampicillin Piperacillin Benzathine penicillin + benzylpenicillin Sulbactam/ampicillin
Less bioavailability than amoxycillin Same molecule as ampicillin Cost/benefit unfavourable; use a ureidopenicillin such as mezlocillin Procaine may be harmful so penicillin alone or benzathine benzylpenicillin would be better
Cost/benefit unfavourable; not available for sequential therapy Clavulanic acid/ticarcillin Cost/benefit unfavourable; not available for sequential therapy Cefuroxime axetil Low bioavailability Cefoperazone Cost/benefit unfavourable Cephalothin Requires from 4 to 6 dose per day; cannot be used with aminoglycosides, frusamide or polymyxin in kidney failure Cefodizime Cost/benefit unfavourable, not shown in vitro pro-host effect Aztreonam Cost/ benefit unfavourable, compared with other aminoglycosides that have a similar spectrum Roxithromycin Older than other macrolides Lincomycin More restricted spectrum and activity than clindamycin Oral clindamycin Greater risk for C. difficile related colitis Netilmicin Cost/benefit unfavourable compared with gentamicin. or amikacin Tobramycin Cost/benefit unfavourable compared with gentamicin Norfloxacin Better to use earlier fluoroquinolones in UTI Ofloxacin Cost/benefit unfavourable compared with ciprofloxacin Oral pefloxacin Cost/benefit unfavourable compared with ciprofloxacin
on special named patient request, whose cost decreased by 52% from 741 000 Euros in 1997 to 356 000 Euros in 1998 (Table 3). This reduction was chiefly due to the use of ceftazidime only in cases when it was specifically needed; in all other cases lower cost alternative were used. Expenditure on tazobactam/piperacillin, another restricted drug, was reduced by 26%; previously due to activity against anaerobic bacteria, it had mainly been used for prophylaxis (Table 3). Imipenem was removed because of significant resistance problems in Gram-negative bacteria. Meropenem was restricted, but the expenditure was similar to that before because carbapenems were administered as sug-
M. Bassetti et al. / International Journal of Antimicrobial Agents 16 (2000) 295–299
298
Table 3 Cost (×1000) of the main antibiotics used 1996–1998 1996 Tazo-piperacillin Meropenem Ceftazidime Ceftriaxone Ceftizoxime Cefotaxime Cefazolin Vancomycin Teicoplanin Amoxy/clav Mezlocillin Ciprofloxacin Aztreonam Imipenem Piperacillin Other antibiotics Total
1997
prophylaxis increased from 1996 to 1998 to 348 and 220%, respectively. 1998
59 879 140 129 702 838 387 902 120 616 106 442 20 217 244 228 311 357 10 087 290 57 135 60 503 279 936 262 631 538 881
189 706 148 209 741 418 373 388 173 902 107 204 19 016 223 056 292 318 22 382 1 074 86 989 81 094 207 790 184 965 433 645
139 489 168 020 355 070 439 675 292 896 213 023 40 606 184 761 375 712 40 878 34 818 12 820 30 890 48 966 0 469 226
3 275 887
3 302 764
2 954 415
gested by TCHF for the ICU and uncomplicated postsurgery infections instead of for surgical prophylaxis or for mild infections. Teicoplanin costs increased by 28% mainly in surgery, but this drug was used only in serious infections due to Gram-positive, resistant bacteria [18]. The DDD values per 100 patients per year are shown in Table 4. Ceftriaxone was the most prescribed drug in SMTH during 1998 and it was used in 4.9 patients each day for 100 patients. Third generation cephalosporins are still the most commonly prescribed drugs in SMTH, as we noticed in previous reports. The use of amoxycillin/clavulanic acid and ceftizoxime most commonly used for sequential therapy of severe infections and the second choice for surgical Table 4 Daily defined dose for 100 hundred patients per day 1996 Tazo/piperacillin Meropenem Ceftazidime Ceftriaxone Ceftizoxime Cefotaxime Cefazolin Vancomycin Teicoplanin Clavulanic acid amoxycillin Mezlocillin Ciprofloxacin Aztreonam Imipenem Piperacillin
0.043 0.41 2.6 4.21 1.2 0.78 0.67 1.1 1.35 0.5 0.004 0.2 0.28 1 1.6
1997 0.142 0.56 3 4.06 1.84 0.85 0.42 1.1 1.34 1.18 0.014 0.32 0.27 0.8 1.25
1998 0.108 0.58 1.33 4.9 3.17 1.68 1.1 1.01 1.73 2.24 0.5 0.45 0.14 0.18 0
5. Conclusions About 500 of named patient requests were made after January 1, 1998, which were evaluated by an infectious disease consultant. There was an initial difficult period when physicians working in SMTH had to acclimatise to the new strategies and rules for antibiotic therapy, but these problems are now resolved. This exercise reduced the use of some antibiotics which were not used properly [19]; the restriction policy has resulted in clear and immediate saving and we hope for an improvement in the future in the bacterial resistance pattern induced by the reduced selective pressure on the same pathogens. Some antibiotics that were less frequently administrated are now correctly used and have replaced others. This improvement in antibiotic choice has resulted in a considerable saving and hopefully a better resistance pattern for the future. Some physicians queried some aspects of this formulary and their observations have helped mould the present policies. The formulary is constantly updated on the basis of microbiological resistance changes and of changes in use of antibiotics. On the basis of the early results of this policy, we suggest this policy could help many other drug categories which are equally expensive and badly used. We hope to optimise the drug use in the future without a restriction policy, but by the provision of improved information for the user.
References [1] Frank MO, Batteiger BE, Sorensen SJ, et al. Decrease in expenditure and selected nosocomial infection following implementation of an antimicrobial- prescribing improvement program. Clin Perform Qual Health Care 1997;5:180 – 8. [2] Jarvis WR. Preventing the emergence of multi-drug microorganisms through antimicrobials use controls: the complexity of the problem. Infect Control Hosp Epidemiol 1996;17:490 –5. [3] McGowan JE. Do intensive hospital antibiotic control programs prevent the spread of antibiotic resistance? Infect Control Hosp Epidem 1994;15:478 – 83. [4] Rahal JJ, Urban C, Horn D, et al. Class restriction of cephalosporins use to control total cephalosporins resistance in nosocomial Klebsiella. J Am Med Assoc 1998;14:1233 –7. [5] Neu HC. The crisis in antibiotic resistance. Science 1992;257:1064– 73. [6] Bryan CS. The role of infectious disease physician in setting guidelines for antimicrobials use. Bull NY Acad Med 1987;63:627 – 37. [7] John JF, Fishman NO. Programmatic role of the infectious diseases physician in controlling antimicrobial costs in the hospital. Clin Infect Dis 1997;24(3):471– 85.
M. Bassetti et al. / International Journal of Antimicrobial Agents 16 (2000) 295–299 [8] Marr JJ, Moffet H, Kunin CM. Guidelines for improving the use of antimicrobial agents in hospitals: a statement by the Infectious Disease Society of America. J Infect Dis 1998;157:869 – 76. [9] Gross PA. Practice guidelines for infectious disease: a rational for a work in progress. Clin Inf Dis 1998;26:1037–41. [10] Coleman RW, Rodondi LC, Keubisch S, et al. Cost-effectiveness of prospective and continuous parenteral antibiotic control: experience at the Palo alto Veterans Affairs Medical Center from 1987 to 1989. Am J Med 90;1991:439–44. [11] Molly T, Shalini G, Moses BV, Abraham J. Monitoring of antibiotic use in a primary and tertiary care hospital. J Clin Epidemiol 1996;49(2):251–4. [12] Eherenkranz NJ. Containing costs of antimicrobials in the hospital: a critical evaluation. Am J Infect Control 1989;17(5):300– 10. [13] Karki SD, Holden JM, Mariano E. A team approach to reduce antibiotic costs. DICP Ann Pharmacother 1990;24:202–5.
.
299
[14] Woodward RS, Medoff G, Smith MD, et al. Antibiotic cost savings from formulary restrictions and physician monitoring in a medical-school affiliated hospital. Am J Med 1987;83:817–23. [15] MacGowan AP, Bowker KE. Sequential antimicrobial therapy: pharmacokinetic and pharmacodynamic considerations in sequential therapy. J Infect 1998;37(1):30 – 6. [16] WHO. Anatomical Therapeutical Chemical (ATC) Classification Index including Defined Daily Doses (DDDs). WHO Collaborating Center for Drug Statistics Methodology, Oslo, 1995. [17] Clark KW, Gray D. The defined daily dose as a tool in pharmacoeconomics. Advantages and limitation. Pharmacoeconomics 1995;7(4):280 – 3. [18] Morgan AS, Brennan PJ, Fishman NO. Impact of vancomycin restriction policy on use and cost of vancomycin and incidence of vancomycin resistant Enterococcus. Ann Pharmacother 1997;31(9):970– 3. [19] Gould IM, Jappy B. Trends in hospital antibiotic prescribing after introduction of an antibiotic policy. JAC 1996;38:895–904.