Inactivation of Quinolone by Feces

Intestinal members of the family Enterobacteriaceae were eliminated in five human volunteers treated with oral ofloxacin for 5 days. No emergence of resistant Enterobacteriaceae was observed. Counts of group D streptococci were significantly reduced. Colonization by Candida sp. was observed in all five volunteers during ofloxacin treatment. The anaerobic flora was fairly stable from one sample to another before treatment and was not substantially modified by ofloxacin.The prospective clinical benefits of fluoroquinolones include their uses in severe bacterial gastroenteritis and selective decontamination of the gastrointestinal tracts of neutropenic patients (6). Elimination of fecal aerobic gramnegative bacteria and concomitant stability of the anaerobic flora have been described after ingestion of norfloxacin (5,8) or ciprofloxacin (3) by human volunteers. It is probably related to the enterohepatic circulation of fluoroquinolones (6). Since another new fluoroquinolone, ofloxacin, is more active in vitro against anaerobic bacteria than are the other fluoroquinolones (9, 10, 12), we thought it of interest to study the effect on fecal bacteria of its administration to human volunteers.Five healthy, fully informed adults received oral ofloxacin twice daily for 5 days in doses of 200 mg. None had taken antimicrobial agents for at least 1 month before the study. Blood samples were drawn on the first and the last days of treatment at 1 h after drug ingestion. Freshly passed fecal samples were obtained once before treatment, daily during treatment, and daily for 1 week thereafter.Fecal anaerobes were counted on Aranki agar in an anaerobic glove box as described earlier (2). In five volunteers, a total of 814 clones which were recovered from 10-8 or 10-9 dilutions of samples obtained before and after 4 days of treatment (82 ± 7 clones per sample) were classified according to their Gram stain properties, shape and positions of spores, and growth characteristics under anaerobic and aerobic conditions, as previously described (8). Anaerobes were classified as oxygen-sensitive or -tolerant strains, based on their resistance to 1 h of exposure to atmospheric oxygen (1).Group D streptococci were counted on bile-esculin agar (Difco Laboratories, Detroit, Mich.), and staphylococci were counted on mannitol-salt agar (Bio-Merieux, Charbonnieres-les-Bains, France). Organisms of the Enterobacteriaceae family were counted on Drigalski agar (IPP, Paris, France) without antimicrobial agents or supplemented with either 4 ,ug of ofloxacin (kindly provided by Diamant Pharmaceuticals) per ml or 4 or 40 ,ug of nalidixic acid (Winthrop Laboratories, Clichy, France) per ml. These media were incubated for 48 h at 37°C. Yeast cells were counted on Sabouraud dextrose agar (Difco) incubated at room temperature for 1 week. The ofloxacin concentrations in human sera and feces were measured by agar diffusion assay (4). Mueller-Hinton agar at pH 7.3 and Klebsiella pneumoniae 1082E were used.Bacterial counts were converted into common logarithms. C...

Section: Cfu/g Of Feces [Individual Data Not Shown])supporting

confidence: 73%

Effect of oral ofloxacin on fecal bacteria in human volunteers

Pecquet¹,

Andremont²,

Tancrède³

1987

“…First, the level of resistance is somewhat surprising given the relatively frequent isolation of strains from the gastrointestinal tract and the presumed entry of the isolates from the gastrointestinal tracts of our bacteremic patients into their bloodstreams. Concentrations of ofloxacin in feces may be as high as 400 ,ug/g (6) or even higher (28 vated drug (28,51), which would allow organisms for which the MICs are lower, such as those observed in the present study, to persist in the flora of the gastrointestinal tract. Such a phenomenon has been observed in experiments with animals (42).…”

Section: Discussionmentioning

confidence: 82%

Emergence of fluoroquinolone-resistant Escherichia coli at a cancer center

Kern¹,

Andriof²,

Oethinger³

et al. 1994

189

Prophylactic treatment with fluoroquinolones of patients with profound neutropenia has been found to be useful for preventing gram-negative bacteremia and has become a standard preventive-therapy strategy in many cancer centers, but the development of bacterial resistance is a cause of concern. During the past few years, we have observed an increasing number of patients with leukemia from whom fluoroquinolone-resistant strains of Escherichia coli were isolated. The increase was significant in this patient population, and among patients with other underlying diseases, the rates of isolation of such strains per number of discharges were significantly lower and did not increase. Most of the leukemia case patients (16 of 19) had been pretreated with an oral quinolone (ofloxacin), with cumulative doses until the first isolation of a resistant E. coli strain ranging from 0 to 97.8 g (median, 14.4 g). Repeated isolation of such strains was seen in 8 of 17 patients during a follow-up period of .4 weeks and in 1 of 6 patients during a follow-up period of .16 weeks. Ten patients developed bacteremia (mortality, 1 of 10). On the basis of the number of patients with leukemia admitted to the hematology-oncology service, the incidence of bacteremia caused by fluoroquinolone-resistant E. coli increased from <0.5% in 1988-1989 and 0.8% in 1990-1991 to 4.5% in 1992-1993 (P < 0.01). MICs for nine isolates obtained from cultures of blood from different patients ranged between 8 and 16 ,ig/ml (ciprofloxacin and PD 131628), 8 and 32 ,ug/ml (ofloxacin and BAY Y 3118), and 16 and 32 ,Lg/ml (sparfloxacin) and indicated resistance to trimethoprim-sulfamethoxazole, ampicillin, doxycycline, and chloramphenicol. Of nine isolates obtained from cultures of blood from different patients and that were subjected to genomic DNA typing by pulsed-field gel electrophoresis ofXbaI digests, seven were typeable. Among these, four different genotypes were identified, suggesting both the independent development and the horizontal spread of resistant clones ofE. coli.Several controlled studies have suggested that oral fluoroquinolones, particularly ciprofloxacin and ofloxacin, may be useful prophylactic antibacterial agents in neutropenic cancer patients (4,9,10,15,22,29,30,56). Fluoroquinolone treatment in these patients was associated with a significant reduction and virtual absence of infections caused by members of the family Enterobacteriaceae, with less fever (8, 39) and a shorter duration of antimicrobial therapy (22,29,39). Such beneficial effects were observed, even though such treatment has rapidly led to the emergence of resistance in gram-positive organisms not infrequently associated with clinical failures of prophylaxis and therapy (11, 16, 23-26, 34, 38, 52, 53, 55 (14,44), and Escherichia coli (2,17,31,35,45). Since enteric bacilli appear to be the primary target organisms of fluoroquinolone prophylaxis in neutropenic patients, increasing levels of resistance to fluoroquinolones in these species, particularly E. coli, would have a maj...

“…Fluoroquinolones are actively secreted into the human and rodent intestinal tract, resulting in intestinal concentrations that are typically 100 to 1,000 times higher than serum concentrations after oral or parenteral dosing (12,16). These agents inhibit susceptible facultative gram-negative organisms in the intestinal tract but have much less effect on intestinal anaerobes than would be predicted based on the drug levels achieved (10,17). For example, the MIC at which 90% of isolates are inhibited of ciprofloxacin for Bacteroides species is 1 to 32 g/ml (18), but this agent achieves concentrations of 185 to 2,220 g/g in stool (3,14).…”

mentioning

confidence: 99%

“…For example, the MIC at which 90% of isolates are inhibited of ciprofloxacin for Bacteroides species is 1 to 32 g/ml (18), but this agent achieves concentrations of 185 to 2,220 g/g in stool (3,14). The minimal impact of the fluoroquinolone antibiotics on intestinal anaerobes has been attributed to high degrees of reversible binding of these agents to fecal matter, reduced susceptibility of anaerobic bacteria to fluoroquinolones under strictly anaerobic conditions, and an inoculum effect for inhibition of anaerobes (10,17).…”

mentioning

confidence: 99%

Effect of Parenteral Fluoroquinolone Administration on Persistence of Vancomycin-Resistant Enterococcus faecium in the Mouse Gastrointestinal Tract

Donskey¹,

Helfand²,

Pultz³

et al. 2004

101

We examined the effect of subcutaneous fluoroquinolone antibiotic administration on persistence and density of vancomycin-resistant Enterococcus faecium stool colonization in mice. Levofloxacin and ciprofloxacin did not promote colonization in comparison to saline controls, whereas moxifloxacin and gatifloxacin promoted persistent overgrowth in a dose-dependent fashion.In a mouse model and in colonized patients, we have demonstrated that antibiotics with potent in vitro activity against intestinal anaerobes promote persistent high-density colonization with vancomycin-resistant Enterococcus faecium (VRE), whereas antibiotics with minimal antianaerobe activity (including ciprofloxacin) do not (4, 5). Although some fluoroquinolone antibiotics have enhanced in vitro activity against anaerobes (e.g., moxifloxacin and gatifloxacin) (1, 13), studies with human volunteers have demonstrated that none of the currently available agents in this class cause a significant reduction in the density of intestinal anaerobes (2,(6)(7)(8)(9)14). Therefore, we examined the effect of fluoroquinolone antibiotics with various levels of antianaerobe activity on the persistence of VRE stool colonization in mice.The mouse model that we have previously utilized to study the effect of antibiotics on persistence of VRE stool colonization was used (4). Male CF1 mice (Harlan Sprague-Dawley, Indianapolis, Ind.) weighing 25 to 30 g were housed in individual cages and fed rodent chow and water ad libitum. VRE colonization with Enterococcus faecium strain C68 was established in all mice by administering oral vancomcyin (250 g/ liter) in drinking water for 2 days before and 5 days after esophageal instillation of 10 8 CFU of VRE in 0.5 ml (4). After discontinuation of oral vancomycin, mice were begun on twice-daily subcutaneous injections of saline (negative controls) or antibiotics for 15 days. Three different doses of the fluoroquinolone antibiotics were studied: a low dose equal to the usual human dose administered over a 24-h period (milligrams of antibiotic per gram of body weight); a medium dose of 5 times the low dose, and a human-equivalent dose of 12 times the usual human dose calculated by the technique of Freireich et al. (11). The dose of levofloxacin was based on the 750-mg-per-day human dose. Gatifloxacin and moxifloxacin were administered only at the lower two dosages because the highest dosage of these agents resulted in significant subcutaneous tissue irritation. The dosages included ciprofloxacin at 0.4, 2, and 4.8 mg/day; levofloxacin at 0.375, 1.875, and 4.7 mg/day; gatifloxacin at 0.2 and 1 mg/day; and moxifloxacin at 0.2 and 1 mg/day. Clindamycin at 1.4 mg/day promoted persistent high-density colonization in previous experiments and was included as a positive control (4).Four mice were included in each experimental group, and the experiments were performed twice (eight mice per group). Stool samples were collected prior to starting subcutaneous antibiotics and then on days 5, 10, and 15 of antibiotic therapy. To measure the de...