Fluoroquinolone consumption and resistance in haematology–oncology ...

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Fluoroquinolone consumption and resistance in haematology–oncology ...

  1. 1. Fluoroquinolone consumption and resistance in haematology–oncology patients: ecological analysis in two university hospitals 1999–2002 Winfried V. Kern1 *, Michaela Steib-Bauert1 , Katja de With1 , Stefan Reuter2,3 , Hartmut Bertz4 , Uwe Frank5 and Heike von Baum6 1 Center for Infectious Diseases and Travel Medicine, Department of Medicine, 4 Department of Haematology- Oncology and 5 Institute of Environmental Medicine and Hospital Epidemiology, University Hospital, Hugstetter Strasse 55, D-79106 Freiburg; 2 Section of Infectious Diseases and Clinical Immunology and 3 Department of Haematology-Oncology, University Hospital and Medical Center; 6 Section of Hospital Hygiene, Department of Medical Microbiology and Hygiene, University of Ulm, Ulm, Germany Received 26 July 2004; returned 21 September 2004; revised 3 October 2004; accepted 23 October 2004 Objectives: To compare rates of in vitro fluoroquinolone resistance of bacterial isolates obtained from inpatients of two haematology–oncology services with high and low fluoroquinolone consumption. Methods: Two hospitals with consistently high (A) and low (B) fluoroquinolone use in their haemato- logy–oncology services between the years 1999 and 2002 were identified in a hospital antibiotic use surveillance project. Rates of in vitro resistance to fluoroquinolones in inpatients of the services were determined for Escherichia coli and coagulase-negative staphylococcal bloodstream isolates, and also for Pseudomonas aeruginosa and Staphylococcus aureus isolates from any site. Results: Fluoroquinolone resistance of E. coli was significantly higher in hospital A than in hospital B, but there was no such correlation between fluoroquinolone use and resistance rates for P. aeruginosa and staphylococci. Conclusion: The impact of antibiotic consumption on the prevalence of resistance may differ widely between different pathogens. Interventions using ecological analyses of the relationship between hos- pital antibiotic use and resistance need to consider pathogen-specific dynamics in the emergence and control of bacterial resistance. Keywords: antibiotic use, Escherichia coli, fluoroquinolone resistance, antibiotic policy, drug utilization, febrile neutropenia, resistance epidemiology, staphylococci Introduction Fluoroquinolones were introduced into clinical practice in the hope of slowing down the development of resistance due to the extremely low likelihood of transferable plasmid-mediated resistance. Fluoroquinolone resistance, however, is now common among many bacterial pathogens worldwide.1–3 Not surprisingly, the most important risk factor for fluoroquinolone resistance appears to be previous fluoroquinolone use.4–7 Reducing quino- lone use through interventions might offer opportunities to reduce the prevalence of bacterial resistance to this class of anti- biotics. Planning such interventions requires information about the relationship between the volume of quinolone use and the prevalence of resistance in different health care settings, patient populations, and drug–pathogen pairs. In a recent hospital antibiotic use surveillance project, we identified two hospitals with consistently high and low fluoroqui- nolone consumption levels in haematology–oncology services over several years. We evaluated the rates of resistance of clinical isolates from inpatients of these services in order to obtain esti- mates for pathogen-specific variations in resistance prevalence as a baseline before intervention. Unexpectedly, there was no corre- lation between unit-wide fluoroquinolone consumption and resist- ance among staphylococci and Pseudomonas aeruginosa, while .......................................................................................................................................................................................................................................................................................................................................................................................................................... *Corresponding author. Tel: +49-761-270-1819; Fax: +49-761-270-1820; E-mail: info@if-freiburg.de .......................................................................................................................................................................................................................................................................................................................................................................................................................... Journal of Antimicrobial Chemotherapy DOI: 10.1093/jac/dkh510 JAC Page 1 of 4 JAC q The British Society for Antimicrobial Chemotherapy 2004; all rights reserved. Advance Access published December 1, 2004 byguestonNovember19,2010jac.oxfordjournals.orgDownloadedfrom
  2. 2. fluoroquinolone resistance of Escherichia coli correlated well with consumption data. Materials and methods Two university hospitals with large differences in fluoroquinolone consumption in the haematology–oncology service were identified after evaluation of antibiotic use data obtained from the hospital pharmacies. This finding was related to the extensive use of oral fluoroquinolones (>90% levofloxacin orally in daily dosages of 1 Â 500 mg in patients with normal renal function) for infection pre- vention in all haematology patients with neutropenia admitted to one of the two hospitals (hospital A), while trimethoprim/sulfa- methoxazole was used as the standard prophylactic regimen for cancer patients with neutropenia in the second hospital (hospital B). The two haematology–oncology services were similar with respect to the number of beds and number of admissions per year with de novo diagnosed acute leukaemia. The number of stem cell or bone marrow transplant recipients was slightly higher in hospital B (yearly number, $ 70 versus 100, respectively). This subgroup of hospital B haematology–oncology service patients received cipro- floxacin (in daily dosages of 2 Â 500 mg) for infection prevention during the neutropenic period following the conditioning regimen. In both hospitals, fluoroquinolones were not recommended as first- or second-line empirical therapy of neutropenic fever. The two hospitals are located in different regions of the federal state of Baden-Wu¨rttemberg where fluoroquinolone consumption in the community has been comparatively low.8,9 Antibiotic use was expressed as defined daily doses per 100 patient days (DDD/100) according to the World Health Organization (WHO)/Anatomical Therapeutic Chemical (ATC) classification (http://www.whocc.no). We also used a different definition of daily doses [prescribed daily doses (PDD), consistent with local guide- lines] since the WHO/ATC classification usually overestimates antibiotic consumption due to its often low defined daily doses com- pared with truly prescribed doses in hospital practice. For example, the WHO/ATC DDD for levofloxacin (according to the WHO/ATC 2001 classification guidelines) is 250 mg, whereas the dose usually prescribed (and also used according to local guidelines in hospital A) was 500 mg per day. Yearly rates of in vitro resistance to fluoroquinolones (cipro- floxacin and/or levofloxacin) in E. coli, other Enterobacteriaceae, P. aeruginosa, other non-fermentative bacilli, Staphylococcus aureus and coagulase-negative staphylococci (CoNS) were retrieved from the microbiology laboratories of the two institutions. Suscepti- bility testing was done according to established guidelines using microbroth dilution tests. Identical breakpoints for resistance were used in the two institutions. Copy strains (isolates from the same patient during a given admission) were excluded. For E. coli and other Enterobacteriaceae, resistance to trimethoprim/sulfamethoxa- zole was also evaluated. We evaluated isolates obtained from any site versus bloodstream isolates separately. We finally only included groups of isolates in this analysis if their mean annual number (tested non-copy isolates) was at least 10 at both institutions. Thus, bloodstream isolates of P. aeruginosa and S. aureus had to be excluded from analysis, and in hospital A, inadequate numbers of staphylococci had been tested for susceptibility to fluoroquinolones in 1999. Also, meaningful comparison of resistance rates in Enterobacteriaceae other than E. coli and in non-fermentative Gram-negative bacilli other than P. aeruginosa was not possible due to major differences in the num- bers of isolates at the two hospitals: there were many more Entero- bacteriaceae isolates from hospital B patients, and conversely, there were many more isolates of non-fermenters in hospital A patients, suggesting distinctive effects of antibiotic use on the spectrum of significant pathogens and presumably patient endogenous flora. Pearson’s correlation coefficient r was used to describe the association between yearly department-wide resistance rates and antibiotic consumption. Results and discussion Hospital A haematology–oncology service showed a fluoroqui- nolone use density of 75 DDD/100 (4-year average, 1999–2002; range, 53.2–92.8) which was significantly higher than at hospital B (4-year average, 12 DDD/100; range, 9–13.2) (Figure 1). Applying the alternative daily dose definition (prescribed daily doses, PDD) to consumption data from the two hospitals, fluoro- quinolone use in hospital A was still much higher than in hospi- tal B (4-year averages, 37.9 versus 10.7 PDD/100) while total consumption of antibiotics was similar in the haematology– oncology services of the two hospitals (81.9 versus 81.4 PDD/100) (Figure 1). Since trimethoprim/sulfamethoxazole was used as a standard prophylactic drug in neutropenic patients in hospital B, consumption of this agent was higher in hospital B than in hospital A (6.3 versus 15.5 PDD/100). As shown in Figure 2, rates of in vitro resistance to fluoroqui- nolones were high in hospital A haematology–oncology service bloodstream isolates of E. coli (range, 64–79%) and relatively low in hospital B (range, 0–10%), and correlated well with the consumption data (Pearson’s correlation coefficient, r = 0.95). Figure 1. Antibiotic use during the years 1999–2002 in the haematology– oncology services of two university hospitals. DDD, defined daily doses according to ATC/WHO; PDD, prescribed daily doses according to local treatment guidelines. Grey bars, fluoroquinolones; black bars, trimethoprim/ sulfamethoxazole; white bars, all other antibacterial agents. W. V. Kern et al. Page 2 of 4 byguestonNovember19,2010jac.oxfordjournals.orgDownloadedfrom
  3. 3. The correlation between use and resistance was less clear for trimethoprim/sulfamethoxazole (r = 0.63) because relatively low consumption of trimethoprim/sulfamethoxazole in hospital A (<10 PDD/100) was associated with relatively high resistance rates in E. coli (range, 33–59%) which were not much lower than those observed in hospital B, and with trimethoprim/sulfa- methoxazole resistance rates in E. coli bloodstream isolates ran- ging between 42 and 76% (Figure 2). A possible explanation for the higher rate of resistance to trimethoprim/sulfamethoxazole compared with fluoroquinolones at similar consumption levels is the more rapid development of resistance to trimethoprim/sulfa- methoxazole via transferable elements together with a higher resistance prevalence in the general population.10–12 Rates of fluoroquinolone resistance in the two services were similar for P. aeruginosa (A, 10–31%; B, 14–29%, Figure 2) and S. aureus (A, 0–12%; B, 3–17%, data not shown) and did not correlate with unit-wide fluoroquinolone consumption (P. aeruginosa, r = À0.05; S. aureus, r = 0.16). Fluoroquinolone resistance rates for S. aureus reflected the MRSA rates in the two services. In contrast, fluoroquinolone resistance rates were much higher in CoNS (A, 68–79%; B, 70–79%), but again, did not correlate with fluoroquinolone consumption (r = À0.05). The results for hospital B did not change when the bone marrow and stem cell transplant unit (where ciprofloxacin was usually given as prophylaxis) was excluded from the analysis (data not shown). These findings show that pathogen-specific patterns of organism–drug interaction obviously depend on organism preva- lence, clonal turnover, and risks to develop resistance in a par- ticular species. The findings are relevant to planning drug use interventions and interesting for several reasons. First, they show a uniformly high prevalence of fluoroquinolone resistance among CoNS even in the low-consumption unit, consistent with the known rapid development of resistance at no or low fitness cost in these organisms,13–17 a possible role of methicillin resist- ance,18–20 and, perhaps, frequent patient-to-patient trans- mission.21,22 The ‘low-consumption’ unit showed fluoroquinolone use of $ 12 DDD/100 which is in the range of that reported for intensive care units from diverse areas, and thus it is only low relative to hospital A.23–26 Whether the specific drug used at hos- pital B (ciprofloxacin) plays a role for the high resistance preva- lence values in CoNS is possible but cannot be judged from this study. Second, the data appear to confirm the view that through restriction of fluoroquinolone use in hospitals, it may be possible to reduce the prevalence of fluoroquinolone resistance in E. coli to the level prevalent in the community as suggested by previous studies.27–29 Third, the situation for P. aeruginosa and S. aureus appears to be different from that for the organisms discussed above. For unknown reasons, both P. aeruginosa and S. aureus have become infrequent pathogens in haematological patients. Low colonization titres and/or infrequent carriage would provide less chance to select for resistant mutants and enable their trans- mission. In addition, fluoroquinolone-resistance mutations in S. aureus and P. aeruginosa may result more frequently in a relevant loss of fitness. Therefore, interventional programmes may be less likely to impact on resistance prevalence in these organisms. This situation may differ in intensive care units with higher rates of transmission and higher endemic rates of MRSA, which appear to be more easily selected after exposure to fluoro- quinolones.18 References 1. Acar, J. F. & Goldstein, F. W. (1997). Trends in bacterial resistance to fluoroquinolones. Clinical Infectious Diseases 24, Suppl. 1, S67–S73. 2. Baquero, F. (1990). Resistance to quinolones in gram-negative microorganisms: mechanisms and prevention. European Urology 17, Suppl. 1, 3–12. 3. Fridkin, S. K., Hill, H. A., Volkova, N. V. et al. (2002). Temporal changes in prevalence of antimicrobial resistance in 23 US hospitals. Emerging Infectious Diseases 8, 697–701. 4. Aparicio, J. R., Such, J., Pascual, S. et al. (1999). Development of quinolone-resistant strains of Escherichia coli in stools of patients with cirrhosis undergoing norfloxacin prophylaxis: clinical conse- quences. Journal of Hepatology 31, 277–83. Figure 2. Rates of in vitro resistance to fluoroquinolones (FQ) and trimetho- prim/sulfamethoxazole (SXT) in the haematology–oncology services of hos- pital A (high FQ use) and hospital B (low FQ use) during the years 1999– 2002; nd, no adequate data. Fluoroquinolone consumption and resistance in haematology–oncology patients Page 3 of 4 byguestonNovember19,2010jac.oxfordjournals.orgDownloadedfrom
  4. 4. 5. Carratala, J., Fernandez-Sevilla, A., Tubau, F. et al. (1996). Emergence of fluoroquinolone-resistant Escherichia coli in fecal flora of cancer patients receiving norfloxacin prophylaxis. Antimicrobial Agents and Chemotherapy 40, 503–5. 6. Lautenbach, E., Fishman, N. O., Bilker, W. B. et al. (2002). Risk factors for fluoroquinolone resistance in nosocomial Escherichia coli and Klebsiella pneumoniae infections. Archives of Internal Medicine 162, 2469–77. 7. Richard, P., Delangle, M. H., Merrien, D. et al. (1994). Fluoroquinolone use and fluoroquinolone resistance: is there an association? Clinical Infectious Diseases 19, 54–9. 8. De With, K., Schro¨der, H., Meyer, E. et al. (2004). Antibiotikaan- wendung in Deutschland im europa¨ischen Vergleich. Deutsche Medizinische Wochenschrift 129, 1987–92. 9. De With, K., Schro¨der, H., Steib-Bauert, M., et al. (2004). Antibiotic consumption in ambulatory care in Germany: a regional NUTS-I level analysis. 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In vitro induction of ciprofloxacin resistance in coagulase-negative staphylococci. Infection 17, 247–8. 14. Monsen, T., Ronnmark, M., Olofsson, C. et al. (1999). Antibiotic susceptibility of staphylococci isolated in blood cultures in relation to antibiotic consumption in hospital wards. Scandinavian Journal of Infectious Diseases 31, 399–404. 15. Utili, R., Tripodi, M. F., Rosario, P. et al. (1996). Different susceptibility of coagulase-positive and coagulase-negative staphylo- cocci to ciprofloxacin. New Microbiology 19, 309–14. 16. Hoiby, N., Jarlov, J. O., Kemp, M. et al. (1997). Excretion of ciprofloxacin in sweat and multiresistant Staphylococcus epidermidis. Lancet 349, 167–9. 17. Gustafsson, I., Cars, O. & Andersson, D. I. (2003). Fitness of antibiotic resistant Staphylococcus epidermidis assessed by compe- tition on the skin of human volunteers. Journal of Antimicrobial Chemotherapy 52, 258–63. 18. Weber, S. G., Gold, H. S., Hooper, D. C. et al. (2003). Fluoroquinolones and the risk for methicillin-resistant Staphylococcus aureus in hospitalized patients. Emerging Infectious Diseases 9, 1415–22. 19. Jarlov, J. O. & Hoiby, N. (1998). Coagulase-negative staphylo- cocci in a major Danish university hospital: diversity in antibiotic susceptibility between wards. APMIS 106, 411–6. 20. Mulder, J. G., Kosterink, J. G. & Degener, J. E. (1997). The relationship between the use of flucloxacillin, vancomycin, aminoglyco- sides and ciprofloxacin and the susceptibility patterns of coagulase- negative staphylococci recovered from blood cultures. Journal of Antimicrobial Chemotherapy 40, 701–6. 21. Hedin, G. & Hambraeus, A. (1991). Multiply antibiotic-resistant Staphylococcus epidermidis in patients, staff and environment—a one- week survey in a bone marrow transplant unit. Journal of Hospital Infection 17, 95–106. 22. Kotilainen, P., Nikoskelainen, J. & Huovinen, P. (1990). Emergence of ciprofloxacin-resistant coagulase-negative staphylococ- cal skin flora in immunocompromised patients receiving ciprofloxacin. Journal of Infectious Diseases 161, 41–4. 23. Bager, F. (2000). DANMAP: monitoring antimicrobial resist- ance in Denmark. International Journal of Antimicrobial Agents 14, 271–4. 24. Bellomo, R., Bersten, A. D., Boots, R. J. et al. (1998). The use of antimicrobials in ten Australian and New Zealand intensive care units. The Australian and New Zealand Intensive Care Multicentre Studies Group Investigators. Anaesthesia and Intensive Care 26, 648–53. 25. Meyer, E., Jonas, D., Schwab, F. et al. (2003). Design of a surveillance system of antibiotic use and bacterial resistance in German intensive care units (SARI). Infection 31, 208–15. 26. Fridkin, S. K., Steward, C. D., Edwards, J. R. et al. (1999). Surveillance of antimicrobial use and antimicrobial resistance in United States hospitals: project ICARE phase 2. Project Intensive Care Antimicrobial Resistance Epidemiology (ICARE) hospitals. Clinical Infectious Diseases 29, 245–52. 27. Gomez, L., Garau, J., Estrada, C. et al. (2003). Ciprofloxacin prophylaxis in patients with acute leukemia and granulocytopenia in an area with a high prevalence of ciprofloxacin-resistant Escherichia coli. Cancer 97, 419–24. 28. Martino, R., Subira, M., Altes, A. et al. (1998). Effect of discontinuing prophylaxis with norfloxacin in patients with hematologic malignancies and severe neutropenia. A matched case–control study of the effect on infectious morbidity. Acta Haematologica 99, 206–11. 29. Delarive, P., Baumgartner, J. D., Glauser, M. P. et al. (2000). Evaluation of antibiotic prophylaxis in neutropenic patients with hematologic malignancies. Schweizerische Medizinische Wochens- chrift 130, 1837–44. W. V. Kern et al. Page 4 of 4 byguestonNovember19,2010jac.oxfordjournals.orgDownloadedfrom

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