Incidence and clinical impact of fluoroquinolone-resistant Escherichia coli in the faecal flora of cancer patients treated with high dose chemotherapy and ciprofloxacin prophylaxis

Sofia Pereaa, Manuel Hidalgoc,*, Alberto Arcedianoc, Maria Jose Ramosa, Carlos Gomezc, Javier Hornedoc, Carlos Lumbrerasb, Dolores Folgueiraa, Hernan Cortes-Funesc and Antonio Rodriguez-Noriegaa

a Division of Microbiology b Infectious Diseases c Medical Oncology, Hospital Universitario ‘12 de Octubre’ , Madrid, Spain


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study evaluated the susceptibility of Escherichia colito quinolones in 72 stool samples collected from 31 patients with solid tumours who had undergone high dose chemotherapy (Hdc) and peripheral blood stem-cell (PBSC) rescue with ciprofloxacin prophylaxis. Samples were obtained at admission, after completing prophylaxis and three months later. All E. coli strains isolated from baseline samples were susceptible to quinolones. Fluoroquinolone-resistant E. coli strains were isolated in 10 (32%) patients in the second sample. In eight of these patients isolates were susceptible 3 months later. No patient developed infection due to fluorquinolone-resistant E. coli.No differences were observed in outcome between patients with susceptible and resistant flora.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
High dose chemotherapy (HDC) with peripheral blood stem-cell therapy (PBSCT) is becoming a widespread strategy for the treatment of a variety of malignant diseases. Solid tumours, mainly breast cancer, have become the most common indication for HDC procedures in the USA and Europe. 1 Despite the use of haematological colony-stimulating factors and PBSCT which accelerate haematological recovery, there is a period of several days of severe neutropenia and mucositis in which there is a high incidence of fever and infection. 2 Prophylactic antibiotics are commonly used to decrease the risk of infection in this situation. Several prospective randomized clinical trials have shown that fluoroquinolone prophylaxis effectively decreases the incidence of Gram-negative bacterial infection and overall infectious-related morbidity. Currently, oral broad-spectrum fluoroquinolones, with or without antimicrobial therapy, targeted to Gram-positive organisms, are commonly used to prevent bacterial infections in patient with solid tumours undergoing HDC with PBSCT. 3

One of the potential problems with the use of fluoroquinolone prophylaxis is the selection of fluoroquinolone-resistant Gram-negative bacilli. There are now several reports which show an increase in the incidence of fluoroquinolone-resistant Gram-negative bacillus infections in cancer patients treated with quinolone antibacterial prophylaxis. 4,5,6 However, this problem has not been studied previously in patients treated with HDC and PBSCT. The aim of our study was to determine the incidence of quinolone-resistant Escherichia coli in faecal flora of patients with solid tumours treated with HDC and PBSCT ciprofloxacin prophylaxis, to assess the duration of colonization by resistant organisms and to analyse its clinical consequences.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
All patients with solid tumours scheduled to receive HDC with PBSCT from August 1996 to August 1997 were eligible for the study. Patients were treated prophylactically with oral ciprofloxacin 500 mg tds. Prophylaxis was begun 48 h before stem cell infusion and was continued until the development of the first episode of fever (defined as an axillary temperature of 38°C measured twice with a 4 h interval or a single temperature of >38.5°C), signs or symptoms of infection, serious adverse effects potentially attributable to the study drug, or recovery to an absolute neutrophil count (ANC) of >500 x10 6 cells/L. Management of febrile episodes followed standard recommendations.

Faecal samples were obtained from all patients at baseline and at the end of the prophylaxis. In those patients with resistant strains, a new sample was obtained 3 months later. Stools were collected in sterile containers and cultured within 2 h of collection. The specimens were plated for qualitative culture by direct streaking. The culture media used were blood agar (bioMérieux, Madrid, Spain), MacConkey agar (bioMérieux) and MacConkey agar supplemented with 0.008 mg/mL of norfloxacin (Sigma Aldrich, Madrid, Spain). E. coli isolates were identified and their susceptibilities were obtained by using automatic methods (DIFCO PASCO, Difco Laboratories Inc., Detroit, MI, USA). The susceptibilities of all fluoroquinolone-resistant strains were confirmed by disc diffusion. On the basis of the criteria of the National Committee of Clinical Laboratory Standards, 7 E. coli was considered resistant to ciprofloxacin when the MIC was >=4 mg/L. Mean values of quantitative variables were compared with the Student’s t-test, while the chi-squared test was employed to analyse categorical data.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Thirty-four consecutive patients were scheduled to receive HDC with PBSCT support during the study period. Three patients were excluded because their baseline faecal samples were not obtained before starting prophylaxis. Thirty-one patients were finally evaluable and a total of 72 stool samples collected from these 31 patients were studied. All the E. coli strains isolated from initial faecal samples were susceptible to fluoroquinolones. This was despite three patients having been given fluoroquinolones during previous episodes of chemotherapy-induced neutropenia.

Fluoroquinolone-resistant E. coli strains were isolated from the faeces in 10 patients (32%) in the second stool sample. The MIC of ciprofloxacin in these isolates ranged from 8 to 64 mg/L. The characteristics of the patients that were colonized with resistant E. coli compared with those colonized with susceptible strains are outlined in the Table. The groups did not differ in any baseline characteristic. The mean number of days with prophylaxis was higher in patients that were colonized with E. coliresistant to fluoroquinolones compared with patients that remained colonized by susceptible strains (8.9 days vs 6.4 days). This difference, however, was not statistically significant. Both groups of patients had a favourable clinical course during their transplant procedure. The appearance of fluoroquinolone-resistant E. coliin faecal flora did not translate into a worse outcome in terms of longer duration of fever, antibiotic treatment, requirements of antifungal therapy or longer hospital stay. No other aerobic Gram-negative bacilli resistant to quinolones were isolated from faeces during the study period. One patient with breast cancer developed bacteraemia due to Serratia marcescens. This strain of S. marcescens was susceptible to fluoroquinolones and was also isolated from an iv cannula. No patient developed a bacteraemia due to a fluoroquinolone-resistant Gram-negative bacillus. Three patients had Staphylococcus epidermidis bacteraemia and one patient had a polymicrobial bacteraemia (S. epidermidisand Bacillusspp.).In most patients, colonization by resistant E. coli was transitory. Eight patients initially colonized with resistant flora harboured susceptible organisms in a third sample obtained 3 months after admission. The two patients that remained colonized with resistant strains in the third month had not received further treatment with quinolones.


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Table. Characteristics of the patients in this study
 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The use of fluoroquinolones prophylaxis in neutropenic patients with cancer has been associated with the emergence of infections with fluoroquinolone-resistant Gram-negative bacilli. In studies conducted in Europe by the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer, there was a parallel increase in the proportion of patients that received prophylaxis with quinolones and the appearance of fluoroquinolone-resistant E. coli bacteraemias. 6 The use of quinolone prophylaxis has been identified as the most important and consistent risk factor for fluoroquinolone-resistant E. coli bacteraemia in patients with cancer and chemotherapy-induced neutropenia. 4 A prospective study which analysed the emergence of fluoroquinolone-resistant E. coli in the faeces of patients with haematological malignancies showed that eight patients out of 25 were colonized with fluoroquinolone-resistant strains after a mean of 10 days of treatment with norfloxacin. One patient developed a bacteraemia with a fluoroquinolone-resistant E. coli. 5

Solid tumours, especially breast cancer, are the leading indication for HDC. Patients with solid tumours differ greatly from those with haematological malignancies in terms of past chemotherapy regimens, previous antibiotic treatment, conditioning HDC regimens and type of haematological rescue. Importantly, the use of PBSCT instead of bone marrow transplantation (BMT) with haematological growth factor support has reduced the length of neutropenia to a median of approximately 10 days. This is significantly shorter than in BMT. 2 All these factors have an important influence on the number and nature of infection complications during HDC. Quinolone-based prophylaxis has produced a dramatic decrease in the incidence of Gram-negative infections and outpatient treatment is commonly used in these patients. 3,9,10 The effect of prophylaxis on the susceptibility of E. coli to quinolones has not been previously addressed in these patients.

In our study no patient was found to be colonized with fluoroquinolone-resistant E. coli on initial sampling. This is not surprising since most of the patients had high risk breast cancer and were treated with HDC early in their disease. Most patients did not show neutropenia at this stage and, therefore, had not needed antibiotic treatment.

Ten patients were colonized by fluoroquinolone-resistant E. coli after a mean of 8 days on prophylaxis. This figure is quite similar to previous reports in patients with haematological malignancies and implies that fluoroquinolone-resistant E. coli can be selected even after short exposure to fluoroquinolones. There was a suggestion that the longer treatment with quinolones was associated with a higher risk of colonization with resistant E. coli; probably because of small patient numbers, this difference was not significant. We did not observe any differences in infectious complications in patients colonized with resistant flora compared with those with susceptible flora. In particular, we did not observe bacteraemia caused by fluoroquinolone-resistant E. coli. There is an increasing interest in giving multiple courses of chemotherapy in short periods of time to increase dose intensity. 9 In such situations the selection of fluoroquinolone-resistant flora during the first transplant might increase the incidence of resistant Gram-negative organisms present during the second course and offset the benefits of prophylaxis.

Patient colonization with fluoroquinolone-resistant E. coli was transitory. Only two patients remained colonized with resistant organisms. One of the major concerns with the unrestricted and widespread use of quinolones in the community is the increasing number of fluoroquinolone-resistant E. coli isolated (mainly from urine specimens). This number is estimated to be approximately 15% of urine cultures in Spain. 10 Given the recovery of normal fluoroquinolone-susceptible flora in many patients shortly after the transplantation, it is very unlikely that prophylaxis in this situation contributed significantly to this figure.


    Acknowledgments
 
Presented in part at the Thirty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, 28 September to 1 October 1997, Toronto, Canada.


    Notes
 
* Correspondence address. Institute for Drug Development, 8122 Datapoint Dr., Suite 700, San Antonio, TX 78229, USA. Tel: +1-210-949-5037; Fax: +1-210-692-7502; E-mail: mhidalgo{at}sacl.org Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 . Gratwohl, A., Hermans, J. & Baldomero, H. (1997). Blood and marrow transplantation activity in Europe in 1995. European Group for Blood and Marrow Transplantation. Bone Marrow Transplantation 19, 407–19.[ISI][Medline]

2 . Schmitz, N., Linch, D. C., Dreger, P., Goldstone, A. H., Boogaerts, M. A., Ferrant, A. et al. (1996). Randomized trial of filgastrim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet 347, 353–7.[ISI][Medline]

3 . Momin, F. & Chandrasekar, P. H. (1995). Antimicrobial prophylaxis in bone marrow transplantation. Annals of Internal Medicine 123, 205–15.[Abstract/Free Full Text]

4 . Carratala, J., Fernandez-Sevilla, A., Tubau, F., Callis, M., Gudiol, F. & Ball, P. (1995). Emergence of quinolone-resistant Escherichia coli bacteremia in neutropenic patients with cancer who have received prophylactic norfloxacin. Clinical Infectious Diseases 20, 557–63.

5 . Carratala, J., Fernandez-Sevilla, A., Tubau, F., Dominguez, M. A. & Gudiol, F. (1996). Emergence of fluorquinolone-resistant Escherichia coli in fecal flora of cancer patients receiving norfloxacin prophylaxis. Antimicrobial Agents and Chemotherapy 40, 503–5.[Abstract]

6 . Cometta, A., Calandra, T., Bille, J. & Glauser, M. P. (1994). Escherichia coli resistant to fluoroquinolones in patients with cancer and neutropenia. New England Journal of Medicine 330, 1240–1.[Free Full Text]

7 . National Committee for Clinical Laboratory Standards. (1992). Performance Standards for Antimicrobial Susceptibility Testing—Fourth Informational Supplement M100–54. NCCLS, Villanova, PA.

8 . Meisenberg, B. R., Miller, W. E., McMillan, R., Callaghan, M., Sloan, C., Brehm, T. et al. (1997). Outpatient high-dose chemotherapy with autologous stem-cell rescue for hematologic and nonhematologic malignancies. Journal of Clinical Oncology 15, 11–7.[Abstract]

9 . Rodenhuis, S., Westermann, A., Holtkamp, M. J., Nooijen, W. J., Baars, J. W., van der Wall, E. et al. (1996). Feasibility of multiple courses of high-dose cyclophosphamide, thiotepa, and carboplatin for breast cancer or germ cell cancer. Journal of Clinical Oncology 14, 1473–83.[Abstract]

10 . Alos, J. I., Gomez-Garces, J. L., Garcia-Bermejo, I., Garcia-Gomez, J. J., Gonzalez-Palacios, R. & Padilla, B. (1993). The prevalence of Escherichia coli susceptibility to quinolones and other antibiotics in community acquired bacteriurias in Madrid. Medicina Clinica 101, 87–90.[ISI][Medline]

Received 20 October 1998; returned 25 November 1998; revised 14 December 1998; accepted 17 March 1999