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Byline: M. Oethinger (1), A. S. Jellen-Ritter (2), S. Conrad (3), R. Marre (3), W. V. Kern (2) Abstract: Escherichia coli with high-level fluoroquinolone resistance were isolated from feces and/or various body sites of 16 cancer patients who were on oral fluoroquinolone prophylaxis. Population analysis of fecal isolates in 11 patients showed that fluoroquinoloneresistantE. coli was the only aerobic gram-negative bacillus present and exhibited a relatively homogenous fluoroquinolone MIC distribution. Molecular typing by pulsed field gel electrophoresis of chromosomal DNA digests or by random amplified polymorphic DNA fingerprinting confirmed the clonal nature of gastrointestinal tract colonization withE. coli. Genotyping of ten colonies picked from the same fecal culture demonstrated identical strains in four of four patients examined. Identical genotypes from the same patient were isolated over prolonged periods of time in 12 of 12 cases examined, with one patient (with the longest follow-up of 14 months) who lost his initial genotype and became persistently colonized with a new genotype. In the 11 patients who developed infection due to fluoroquinolone-resistantE. coli, molecular typing also indicated that fecal colonization was associated with, and presumably preceded infection due to an indistinguishable genotype of fluoroquinolone-resistantE. coli. Author Affiliation: (1) Institut fur Laboratoriumsmedizin und Transfusionsmedizin, D-32545, Bad Oeynhausen (2) Sektion Infektiologie und Klinische Immunologie, Medizinische Universitatsklinik und Poliklinik, D-89070, Ulm (3) Institut fur Mikrobiologie und Immunologie, Universitatsklinikum, D-89070, Ulm, Germany Article History: Registration Date: 29/11/2007 Received Date: 07/01/1998 Accepted Date: 08/08/1998

The aim of the present study was to investigate the epidemiologic evolution of fluoroquinolone resistance of E. coli clinical isolates from patients admitted to a hematology-oncology service where fluoroquinolone prophylaxis during neutropenia was recommended as the standard of care for many years but was then discontinued in a trial conducted in patients with acute leukemia. Fluoroquinolones had been shown to decrease the incidence of gram-negative bacteremia in cancer patients with neutropenia, yet it was thought that the emergence of resistance in Escherichia coli and other gram-negative bacteria may have caused a progressive lack of efficacy of fluoroquinolone prophylaxis. Epidemiologic surveillance of fluoroquinolone resistance of E. coli clinical isolates at our cancer center since 1992 showed a continuing influx of new clones not previously observed in the population of cancer patients, an increase in the number of cancer patients per year colonized and/or infected by fluoroquinolone-resistant E. coli (1992-1994, 10-16 patients; 1995-1997, 24-27 patients), and a resistance rate of >50% among E. coli bloodstream isolates of hematology-oncology patients. A 6-month fluoroquinolone prophylaxis discontinuation intervention trial in 1998 suggested that despite increasing resistance among E. coli isolates, fluoroquinolone prophylaxis in acute leukemia patients was still effective in the prevention of gram-negative bacteremia (incidence rates, 8% during the pre-intervention period vs. 20% after discontinuation; p<0.01). The resumption of fluoroquinolone prophylaxis in acute leukemia patients thereafter decreased the incidence of gram-negative bacteremia to the pre-intervention level (9%; p=0.03), while the proportion of in vitro fluoroquinolone resistance in E. coli bacteremia isolates again increased (from 15% during the intervention period to >50% in the post-intervention period). Relative rates of resistance thus were a poor indicator of the potential clinical benefits associated with fluoroquinolone prophylaxis in cancer patients.

Two different proliferation assays have been used to measure the proliferative potential of IgG-fractions from 57 patients with nontoxic goiter of an iodine-deficient area: primary human thyroid epithelial cells (TEC) and the thouroughly investigated FRTL-5 cell line. IgG-fractions from patients with nontoxic goiter (n = 30), nontoxic recurrent goiter (n = 8), toxic-nodular goiter (n = 15) and carcinoma of the thyroid (n = 4) were highly purified on DEAE-Sepharose and additionally Protein A-Sepharose in some cases. The two proliferation assays gave contradictory results: primary cultures of human thyroid epithelial cells (TEC) could not be stimulated by any of the patient's IgG-fractions nor by bTSH. The FRTL-5 cells, however, were stimulated with 10 microU/ml bTSH by 326% +/- 96% (range: 222% - 497%, p less than 0.001). In one experimental series, 72% of all patients exceeded mean + 2 SD of normal controls, when the stimulation index was referred to the effect of bTSH (NTG: 77%, Rec. G.: 88%, Tox. G.: 53%, Ca. thyroid: 75%). With a different method of calculation - stimulation index referred to the basal value - the number of patients above mean + 2 SD of normal controls decreased to 30% (NTG: 33%, Rec. G.: 12.5%, Tox. G.: 33%, Ca. thyroid: 25%). Statistical analysis, however, of results of different patient groups compared to the normal control group failed to show any significance.