A Alvarez, T Gallego, MA Garcia, A Gonzalez-Praetorius, M Martinez, MC Molina, F Garcia Pharmacy service, hospital general de Guadalajara, Spain

INFLUENCE OF ANTIBIOTIC SUSCEPTIBILITY TEST RESULTS ON THE CHANGE OF CIPROFLOXACIN AND OFLOXACIN-BASED TREATMENTS
AIM: To evaluate the influence of antibiotic susceptibility test (AST) results on the medical prescription of ciprofloxacin (C) and ofloxacin (O). MATERIALS AND METHODS: Patients treated with either C or O during a 2-month period were selected. A data sheet was designed to record admission and discharge date, application for microbiological culture and susceptibility-based antimicrobial recommendations, antibiotic therapy and prescribers department. Regimens were classified as treatments with C or with O and as empirical or non-empirical (documented treatments) at the beginning of therapy. Any change based on the AST results in the group of treated patients was studied. RESULTS: Most cases were treated with C. The use of these antibiotics is mainly empirical. Empirical therapy did not match that recommended by the microbiology service in any case, and in 21.7% of the cases the antibiotic was changed to that suggested by microbiology. Among the non-empirical treatment group, the recommended antibiotic was chosen in 30% of the cases. CONCLUSION: The high number of empirical treatments and low rate of attention to microbiological diagnosis indicate an inadequate use of hospital resources. KEY WORDS: Ciprofloxacin, ofloxacin, antibiotic susceptibility, clinical use INTRODUCTION Quality control measures in healthcare attempt to optimize therapeutic outcomes. Although traditional efforts have been designed to contain costs by limiting the use of resources and targeting prescriptions, the variability in prescription practices related to infectious diseases could be managed by paying attention to hospital-specific information, such as the range of susceptible microorganisms and bacterial resistance. Due to potential emerging resistance, some antibiotics should be reserved for the treatment of infections in which standard agents cannot be used. Isolation and identification of pathogens and antibiotic sensitivity testing should be performed before treatment. The general hospital of Guadalajara is a medium-sized hospital with 400 beds, in which the cost of antimicrobial agents accounted for 20.5% of the hospitals total drug expenditure in 1995 and 20.9% in 1996. Eighty-five Defined Daily Doses/100 Daily-Stays (DDD/100DS) were consumed in 1995 and 70.2 in 1996. Ciprofloxacin represented 2.9% of these (2.46 DDD/100DS) in 1995 and 4.1% (2.83 DDD/100DS) in 1996 and the consumption of ofloxacin was 1.4% (1.22 DDD/100DS) in 1995 and 1.95% (1.37 DDD/100DS) in 1996. This was despite the recommendations from microbiology and pharmacy departments, based on information about the increasing emergence of resistance to fluoroquinolones reported in Escherichia coli isolated from urine, published in our hospitals Pharmacy and Therapeutic Committee Bulletin in March 1994 and Interactions with Fluoroquinolones published on June 1992. On the basis of these data, our hospitals Antibiotic Policy and Infectious Diseases Committee edited the guidelines for surgical prophylaxis and empirical antimicrobial treatment. The emergence of resistance to these fluoroquinolones has been reported in most Gram-negative bacteria. However, in 1996, 77% of E. coli isolated in our hospital and 95% of Proteus mirabilis

remained susceptible to ciprofloxacin. We decided to study several aspects of the prescribing of these agents, because of the high percentage of the hospitals total drug expenditure accounted for by fluoroquinolones and the increasing number of reports of rapidly emerging resistance to these antimicrobial agents among both Gram-negative and Gram-positive organisms [6,13,15]. The main purpose of this study was not to evaluate the general use of fluoroquinolones, but to evaluate the influence of antibiotic susceptibility test (AST) results on physicians prescription of ciprofloxacin and ofloxacin.

MATERIALS AND METHODS This was an observational study conducted during a 2-month period from May to June 1996 in the General Hospital of Guadalajara (Spain). Patients receiving either ciprofloxacin (C) or ofloxacin (O) were identified by the departmental log report provided by the computerized unit dose distribution system (UDDS) working on all in-patient units except for the paediatrics department and the intensive care unit. A standardized form was designed to collect the following information about these patients and their quinolone-based regimens: Patient demographic data (age, sex), dates of admission and discharge obtained from the UDDS (the unit dose program is integrated in the general network with a terminal in every nursing unit), diagnosis related to the use of quinolones, prescribers specialty, type of infection and updated drug profile. Quinolone-based treatments: selected quinolone, route of administration and duration of the regimen. Bacteriological examination: date of application, samples assessed, microorganisms isolated and susceptibility-based antimicrobial recommendations performed by the microbiology service. The physician receives the microbiological information within 2 days (4 days if sought just before a non-working day). All regimens were classified in the following groups: treatments with C or O and empirical or documented treatments (this is when the drug prescribed matched AST results). Additionally, the preventive medicine department community-acquired infections. reported all cases of nosocomial or

We defined as a case the study of every C or O regimen associated with isolation and identification of a likely pathogen, and any antimicrobial sensitivity tests performed were assessed. If cultures did not confirm any infectious agent, patients were excluded because an AST was not performed. It was considered to be a positive response when the physician followed the recommendations from the microbiology unit concerning the antimicrobial agent of choice. We also evaluated the appropriateness of prescriptions, with and without bacteriological study, having as a basis the criteria developed from the literature and the hospitals guidelines.

RESULTS AND DISCUSSION

A total of 117 patients receiving treatment with either C or O were identified (87 with C and 30 with O). The mean age was 65 years. Bacteriological examination was requested in only 62 cases (53%). In 35 samples out of 35 patients (29.9%) a likely bacterial pathogen was isolated and AST performed. Four patients were not evaluable because no medical records were available. Finally, 33 C/O regimens were studied (two patients received two treatments). Twenty-two of the patients had urinary tract infections, 5 had skin and soft-tissue infections, 4 had bacterial diarrhoea, 1 had febrile neutropenia and one had acute peritonitis. Table 1 shows the therapeutic regimens and the prescribers positive response to the AST results. Quinolones were used as empirical therapy in 23 of the 33 cases (69.7%) where antibiotic sensitivity tests were performed: 10 patients received C (43.5%) and 13 received O (56.5%). Fourteen out of 22 cases had urinary tract infections, 4 had skin and soft-tissue infections, 3 patients suffered bacterial diarrhoea and 2 cases presented febrile neutropenia and acute peritonitis respectively. Empirical Treatments + Sensitivity Test performed 23 Non empirical Treatments (documented cases) 10 OFLOXACIN: 13 CIPROFLOXACIN: 10 PRESCRIBERS OFLOXACIN: 1 CIPROFLOXACIN: 9 POSITIVE RESPONSE

8 cases 5 Empirical treatments 3 Documented cases

Neither C nor O was recommended

In 2 cases C was recommended In 1 case O was recommended

Figure 1. Type of treatments and antibiotic susceptibility test response.

NOSOCOMIAL 14 cases 23 Empirical treatments 10 cases PRESCRIBERS POSITIVE RESPONSE 2 cases 10 Documented treatments 4 cases PRESCRIBERS POSITIVE RESPONSE 1 case Table 1. Nosocomial and community-acquired Infections.

COMMUNITY-ACQUIRED 19 cases 13 cases 3 cases 6 cases 2 cases

Ten patients (30.3%) received documented treatments: 9 with C (90%) and 1 with O (10%). These patients had urinary tract infections in 8 cases, skin and soft-tissue infections in one case and bacterial diarrhoea in another case. Prescribers responses were positive in 8 cases (24.2%): - In 5 empirical treatments (21.7%), 3 with C and 2 with O in which neither C nor O were recommended by the AST results, the prescriber changed the fluoroquinolone to the antimicrobial agent recommended by the microbiology service. - In 3 of the documented cases (30%) the choice of antimicrobial agents was made on the basis of the bacteriological data: 2 of 9 with C and one with O, which was the suggested agent (this culture was assessed in the ambulatory medical care setting, where sensitivity testing had been performed using disks containing O). Table 2 shows additional information about the selected regimens in each nosocomial or community-acquired infection: There were 14 nosocomial infections. Ten cases were empirically treated and only in 2 did physicians follow the recommendations from the microbiology department. Four nosocomial infections were documented cases, and in only 1 did the physician follow the microbiological recommendations. This case was a complicated urinary tract infection due to Stenotrophomonas (Xantomonas) maltophylia resistant to fluoroquinolones. There were 19 community-acquired infections. The response to microbiological recommendations was positive in 3 out of the 13 empirically treated. There were 2 complicated urinary tract infections caused by resistant strains of E. coli and Ps. aeruginosa treated with C and O respectively, despite bacteriological studies. Six community-acquired infections were documented cases, of which only 2 were treated according to the microbiological information. Microbiology service policy concerning the information of quinolone sensitivity is as follows: Until 1997, susceptibility to C or O was reported only if the isolated pathogen was norfloxacin-resistant. In January 1997, this department decided to include susceptibility to O just in those norfloxacin-resistant cases, while C was never considered the quinolone of choice. This measure was taken due to similar indications, spectrum of activity and adverse effects profiles shared by both fluoroquinolones, while treatments with O were cheaper. Thus, C should only be used to treat susceptible Gram-positive bacterial infections when others agents cannot be used. We consider that it would be interesting to repeat this study during a period in which physicians did not know the susceptibility to ciprofloxacin and to compare the results obtained. In the evaluation of the appropriateness of the different regimens, the following cases met indications for use criteria: Treatments with no isolation request: 41 of 55 initially included were evaluable (no medical report available in 7 and discrepancies about drug administration were observed in 5 patients). Some 18 C/O prescriptions (43.9%) were clinically justified. Cases in which antibiotic susceptibility tests were performed: 3 documented infections of 33 in which bacteriological study and AST were performed followed established criteria (9%) and C and O were justified in all empirical treatments.

Therefore, only 21 out of 74 (28.4%) cases met indications for use criteria. These results reflect the low adoption of protocols for antibiotic use in our hospital. CONCLUSIONS Ciprofloxacin was more widely used than ofloxacin and most cases with O were empirical treatments (only one was a documented case). A possible explanation could be that C was the fluoroquinolone recommended by the microbiology service in the AST results until January 1997. After this date, sensitivity tests already included a disc containing O. In spite of this, the high number of empirical treatments without use criteria and the low rate of attention to microbiological diagnosis indicate a less than optimal use of hospital resources. This has potential consequences, including the emergence of resistance to fluoroquinolones and increased healthcare costs in some cases. The frequency of treatments with C/O that met indications for use criteria was higher in the group without an application for culture, although it was generally lower than expected. The highest percentage of positive responses to antibiotic susceptibility tests was associated with community-acquired infections, although there are no important differences between nosocomial cases and documented treatments. These are only observational data because no statistical method has been applied to the results. C and O used as empirical therapy should follow hospital guidelines with subsequent modifications based on the literature and departmental experiences, and it is necessary for the Antibiotic Policy and Infectious Diseases Committee to evaluate more frequently the use of antibiotics in our hospital to rationalize the use of these drugs. Acknowledgements We thank the microbiology service from the Guadalajara hospital for its valuable help. References [1] Antibiotic Policy and Infectious Diseases Committee from the hospital of Guadalajara (Spain). Guidelines of surgery prophylaxis and antimicrobial therapy 1996. [2] Fass RJ, Barnishan J, Ayers LW. Emergence of bacterial resistance to imipenem and ciprofloxacin in a university hospital. J Antimicrob Chemother 1995; 36(2): 34353. [3] Kresken M Hafner D, Mittermayer H et al for the Bacterial Resistance Study Group, Paul Ehrlich Society for Chemotherapy. Prevalence of fluoroquinolone resistance in Europe. Infection 1994; 22 (suppl 2): 908. [4] Maddix DS, Warner L. Do we need an intravenous fluoroquinolone? West J Med 1992; 157: 559. [5] American Society of Hospital Pharmacists. Criteria for drug use evaluation. Vol 4 1993. - McColl MP, Briceland LL, Lomaestro B. Assessment of empiric antimicrobial use in a teaching hospital. Hosp Pharm 1997; 32: 83944. - White CA, Atmar RL, Wilson J, Cate TR, Stager CE, Greenberg SB. Effects of requiring prior authorization for selected antimicrobials: expenditures, susceptibilities, and clinical outcomes. Clin Infect Dis 1997; 25: 2309. - Gysseus IC, Geerligs LEJ, Doay JMJ et al. Optimising antimicrobial drug use in surgery: an intervention study in a Dutch university hospital. J Antimicrob Chemother 1996; 38: 100112. - Speirs GE, Fenelon LE, Reeves DS et al. An audit of ciprofloxacin use in a district general hospital. J Antimicrob Chemother 1995; 36(1): 2017. - Durand-Gasselin B, Leclercq R, Girard-Pipau F et al. Evolution of bacterial susceptibility to antibiotics during a six-year period in a haematology unit. J Hosp Infect 1995; 29(1): 1933.

- Underhill EJ. Why IV antibiotics? Eur Hosp Pharm 1995; 1(4): 1559. - Rovers JP, Bjornson DC. Assessment of methods and outcomes: using modified inpatient ciprofloxacin criteria in community-based drug use evaluation. Ann Pharmacother 1994; 28(6): 7149. - Pickering TD, Gurwitz JH, Zaleznik D, Noonan JP, Avorn J. The appropriateness of oral fluoroquinolone prescribing in the long-term care setting. J Am Geriatr Soc 1994; 42(1): 2832. - Cooke J, Cairns CJ, Tillotson GS et al. Comparative clinical, microbiologic, and economic audit of the use of oral ciprofloxacin and parenteral antimicrobials. Ann Pharmacother 1993; 27(6): 7859. - Davey P, Dodd T, Keer S, Malek M. Audit of IV antibiotic administration. Pharm J 1990; 244: 7936. - Modai J, The French Multicenter Study Group. Treatments of serious infections with intravenous ciprofloxacin. Am J Med 1989; 87 (suppl 5A): 243S7S.

Address for correspondence A Alvarez Pharmacy service Hospital General de Guadalajara Donante de Sangre S/N 19002 Guadalajara Spain Email: AALVAREZDI@NEXO.ES