Ofloxacin and the gastrointestinal tract: a potential role in the treatment of bacterial enteritis

Journal of Antimicrobial Chemotherapy (1990) 26, Suppl D, 45-53 Ofloxacin and the gastrointestinal tract: a potential role in the treatment of bacterial enteritis R. Lang, M. Lbhner, S. Segev and E. Rubinstein Infectious Diseases Unit, Meir hospital Kfar-Saba and the Infectious Diseases Unit Cham Sheba Medical Center, Tel Aviv University School of Medicine, Israel Ofloxacin is highly active against most pathogens causing bacterial enteritis. High faecal levels are achieved readily following a single oral dose and may persist for up to five days despite partial binding by faeces. In addition, adequate ofloxacin levels persist in pancreatic secretions and bile for 12 to 14 h following oral administration. Clinical data from various centres demonstrate a prompt response when ofloxacin is administered once-daily for shigeuosis, sahnonellosis and various other enteric pathogens. These theoretical observations and clinical data suggest a potential for once-daily oral ofloxacin therapy for bacterial diarrhoea. Introduction Enteric pathogens cause significant morbidity and mortality world wide, particularly in developing countries. Many drugs have been effective in the management of bacterial diarrhoea, but the emergence of resistant pathogens, especially shigella and salmonella strains, has become a major therapeutic obstacle. Patients' compliance with prolonged therapy is also troublesome especially in underdeveloped countries where lower socioeconomic classes are commonly affected. Antibiotics that have activity against most enteric pathogens, that can be administered orally once daily, and that attain prolonged faecal concentrations may prove equally effective or superior to other drugs in the management of bacterial enteric infections. We have reviewed the data concerning the effects of ofloxacin on the gastrointestinal flora, aspects of its pharmacokinetics and its efficacy in the treatment of gastrointestinal infections and suggest its advantages as a once daily oral regimen in the management of bacterial enteritis. Ofloxacin and oral flora Effects of ofloxacin on gastrointestinal flora Single dose. Edlund et al. (1988) found only a small effect of ofloxacin, administered as a single oral dose of 400 mg, on the oral microflora of patients undergoing gastric surgery. Branhamella strains were significantly reduced in numbers and returned to normal within a few weeks but the number of streptococci, micrococci and corynebacteria remained unchanged. Colonization with Gram-negative rods occurred Reprint request* to: E. Rubinstein, MD, Infectious Diseases Unit, Sheba Medical Center, Israel 52621. 03O5-7453/9O/26DO45 + 09 $02.00/0 45 1990 The British Society for Antimicrobial Chemotherapy

46 R. Lang tf al during the study period in four of the 24 patients studied. Except for one patient in the latter group, the total concentration of Gram-negative rods isolated was < lo^/ml saliva. The anaerobic microflora was unaffected by ofloxacin except for suppression of Veillonella spp. between day 2 and day 7 in five of the 24 patients. Repeated dose. Kern, Kurrl & Vanek (1987) studied the changes in the oropharyngeal flora following prolonged ofloxacin therapy given as prophylaxis in profoundly granulocytopenic patients. A rapid and complete elimination of Enterobacteriaceae was observed within one week. Colonization with Pseudomonas aeruginosa and other Gram-negative bacilli occurred in a few patients. Coagulase-negative staphylococci were present in 15% of oropharyngeal washings and their incidence increased after the third week of ofloxacin treatment. Yeasts were found in 28% of oropharyngeal washings. Ofloxacin and gastric flora Single dose. Edlund et at. (1988) investigated the effect of a single oral dose of 400 mg ofloxacin on gastric microflora. Both anaerobic and aerobic bacteria were suppressed in the gastric secretions for 24 h. In six patients, no bacteria were detected on day 0, while five other patients had > 10 5 /ml. The number of bacteria was significantly higher when the ph was > 3-5 than it was when the ph was < 3-5 owing either to a more favourable environment for bacterial proliferation or to more optimal conditions for drug activity. During the study, colonization with yeasts was seen in 13 patients, six of whom had > lo'cfu yeasts/ml of gastric secretions. In 15 of 20 patients studied after four weeks, > 10 5 cfu yeasts/ml gastric secretions were detected. Ofloxacin and the faecal microflora Repeated doses. Pecquet et al. (1987) administered 400 mg ofloxacin daily for five days to five normal volunteers. The faecal concentration of Enterobacteriaceae dropped sharply after administration and no strains were detectable in faeces for four days following discontinuation of the drug. Six days after stopping the drug the number of Enterobacteriaceae in faeces had not returned to pretreatment levels. The same pattern was also observed for enterococci, except that return to pretreatment levels was reached within four days of stopping drug therapy. In addition, all the volunteers were colonized with Candida spp., albeit in small numbers, after four days of treatment. Anaerobic bacteria, on the other hand, remained in concentrations > 10 10 cfu/g faeces. Emergence of resistance to ofloxacin in the intestinal flora was not observed. Shah et al. (1987) reported the effects of 200 mg of ofloxacin administered bd for seven days to ten volunteers. Escherichia coli were not detectable by the third day and continued undetectable until four days after drug discontinuation. Therapy had no effect on the number of anaerobic streptococci, Bacteroides spp., bifidobacteria, Eubacterium spp. and Candida spp. Clostridium difficile and staphylococci were not detected at any time. Enterococci were detected both before and after therapy in some volunteers. Chida et al. (1984) studied the effects of ofloxacin on the human faecal flora in relation to faecal drug concentrations. Five volunteers received 200 mg tds for six days. The elimination time for Enterobacteriaceae from the faeces was 48 h. More than a week was required for the reappearance of the normal enteric flora. Most anaerobes

Ofloxadn and the got 47 remained unaffected. Lecithinase-negative clostridia increased, while lecithinascpositive clostridia decreased during the drug administration. The microflora returned to normal only after four to five weeks. The alterations in faecal flora correlated with the faecal concentrations of ofloxadn. Van-Saene, Lemmetus & Van-Saene (1988) studied the effect of ofloxadn in 15 healthy volunteers who received 200 mg bd for two weeks. Escherichia coli was eliminated after three days of ofloxadn administration and did not reappear until five days after ofloxadn discontinuation. Ofloxadn therapy was assodated with a slight decrease in Enterococcus fecalis numbers during therapy. Half the volunteers had yeast colonization after seven days of therapy. Leigh et al. (1988) studied 11 volunteers who were given 200 mg ofloxadn bd for 3-5 days. Aerobic. Gram-negative badlli were reduced to unrecordable numbers. Gram-negative bacilli reappeared between three and 21 days after the last dose and between one and 21 days after the elimination of ofloxadn activity from the faeces. The total number of aerobes was not significantly different in eight volunteers, as the loss of Gram-negative badlli was balanced by an increase in Gram-positive organisms. No change was seen in the total number of anaerobic bacteria. No significant changes were observed in the number of yeasts. Pre- and post-treatment isolates of the major bacterial spedes were tested for drug resistance to ofloxadn; no change in MICs was detected. Kern et al. (1987) administered 200 mg ofloxadn bd to 40 patients for periods of 14-81 days (mean 35 days), in combination with amphoteridn B suspension. Enterobacteriaceae were completely eliminated from the faeces within one week. Anaerobic micro-organisms were only partly affected by ofloxadn treatment. Coagulase-negative staphylococd were present in 19% of faecal samples and their inddence increased after the fourth week of treatment. Yeasts were observed in 30% of cultures. Resistant strains of aerobic Gram-negative badlli (including a few strains of Ps. aeruginosa) were acquired in four patients. Single dose. Edlund et al. (1988) studied the effect of a single oral dose of 400 mg ofloxadn on faecal flora in 24 patients undergoing gastric surgery. The flora was markedly affected during the seven days of investigation. By day 2, Enterobacteriaceae were eliminated in 12 patients and suppressed in an additional eight. Enterococd, lactobacilli, bifidobacteria, Eubacterium, Veillonella and Bacteroides spp. were also markedly suppressed. Anaerobic coed and clostridia, however, remained unaffected during the study period. In samples obtained four weeks later, the faecal flora had returned to normal. Inactivation and binding of ofloxadn by faeces Van-Saene, Van-Saene & Leek (1986) studied the inactivation of ofloxadn by faeces. The MBCs of ofloxadn for six Gram-negative badlli (Esch. coli, FQebsiella, Enterobacter, Proteus, Pseudomonas and Acinetobacter spp.) were determined in the presence of increasing concentrations (0, 10%, 20%, 30%) of faeces. After incubation, the organisms were subcultured on selective media. The MBCs of ofloxadn for Esch. coli increased dramatically to 6-2 mg/1 after adding 30% faeces. The most resistant strains were Pseudomonas and Acinetobacter spp. that had MBCs of 50 and 100 mg/1 respectively after 30% faeces was added. Reeves (1986) reported that the activity of quinolones may be markedly reduced in

48 R. Lang et al the gastrointestinal tract owing to binding to normal faeces. Edlund, Lindqvist & Nord (1988) measured the binding of quinoloncs to faeces. Analysis revealed two different classes of binding, one specific and the other non-specific. Their results with radioactive norfloxacin showed that the specific binding of quinolones to faeces was a reversible saturable process that increased linearly with faecal concentrations. Of interest was the demonstration that the quinolones may bind to the bacteria present in faeces rather than to faecal fibres and food remnants. They suggested that the increase in MICs, also observed by Van Saene et al. (1986), is due to the quinolone binding to the bacterial mass itself. The concentrations of quinolones assayed in faeces may, therefore, not relate to the free concentration available. In-vitro data Ofloxadn activity against enteric pathogens Bacterial pathogens associated with travellers' diarrhoea. Inagaki et al. (1989) investigated the in-vitro activity of ofloxacin against various pathogens associated with travellers' diarrhoea. Ofloxacin was highly active against 25 strains of enterotoxigenic Esch. coli (MIC*, 0-10 mg/1), 25 strains of Salmonella spp. (MIC*, 0-20 mg/1), 25 strains of Shigella spp. (MIC*, 078 mg/1), 21 strains of Campylobacter jejuni (MIQ,, 0-78 mg/1) and 12 strains of Vibrio parahaemolyticus (MIC*, 0-78 mg/1). Ofloxacin kinetics in the gastrointestinal tract Ofloxacin concentration in saliva, gastric secretions and gastric mucosa Repeated doses. Leigh et al. (1988) studied the concentration of ofloxacin in the saliva of 17 volunteers given ofloxacin 200 mg bd. Mean C,,,,, was 1-9 ±0-7 mg/1 after the first dose, rising to 2-6 ±0-7 mg/1 after the seventh dose. There was a good correlation between salivary and serum concentrations. Kern et al. (1987) found mean peak levels of ofloxacin in saliva and serum of granulocytopenic patients of 1-89 and 118 mg/1 respectively. Single dose. Edlund et al. (1988) studied ofloxacin levels in saliva, gastric secretions and gastric mucosa following a single 400 mg dose of oral ofloxacin. On day 2, eight saliva samples contained 0-1-0-7 mg/1, but in others, ofloxacin could not be detected. The mean ofloxacin concentrations in gastric secretions were 240 mg/1 during surgery (day 1) and 12-4 mg/1 on day 2. Samples of gastric mucosa obtained during surgery 2-4-8 h following ofloxacin administration contained 0-1-11-7 mg/kg (mean 50mg/kg). The mean gastric mucosa/serum concentration ratio was 1-9 and was highest in tissues removed 4-5 h after drug administration. Faecal concentrations of ofloxacin Pecquet et al. (1987) gave 200 mg ofloxacin bd for five days to five volunteers. Mean peak serum concentration of ofloxacin rose from 2-8 ±1-4 mg/1 on day 1 of treatment to 4-2 ± 1-6 mg/1 on day 5. Faecal ofloxacin concentrations were much higher and peaked at 327 ±274 mg/kg faeces after four days of treatment. Five days after therapy, no activity was recovered in the faeces. Leigh et al. (1988) found faecal levels of 1-8-22 mg/g on the second day of therapy and 33-5 98 mg/g on day 4. Ofloxacin was detectable in the faeces of all volunteers one

OSoxadn and the gut 49 day after the last dose, and in six volunteers drug was still present four or five days later. No drug activity could be detected in the faeces on the sixth day following cessation of therapy. Ofloxacin penetration into mesenteric lymph nodes Stahl et al. (1988) studied the distribution of ofloxacin into mesenteric lymph nodes. Ten patients who were to undergo abdominal surgery for non-infective conditions, received four doses of 200 mg ofloxacin. Concurrent samples of the mesenteric lymph nodes and serum were obtained 4-6 h after the last dose. Ofloxacin levels ranged from 0-54 to 6-36 mg/kg. Although the data demonstrate variability between patients, both in absolute drug levels and in the ratio to serum levels, the authors conclude that the ofloxacin levels obtained were all higher than the MIC^, of Salm. typhi, a finding that could explain the clinical efficacy of ofloxacin in the management of typhoid fever. Ofloxacin concentrations in the hepatobiliary system Repeated doses. Kazmierczak et al. (1987) studied ofloxacin levels in the biliary tracts of six patients who underwent cholecystectomy or who had a T-tube drain in their common bile duct. Both groups received seven doses of ofloxacin 200 mg, given orally bd. In the patients with T-tubes, mean levels in bile were 6-5 ±31 mg/1 2-4 h after the first dose and 120±4-6mg/1 1-4h after the seventh dose. In patients undergoing cholecystectomy ofloxacin concentrations in bile from the gallbladder and common bile duct, 6h after the seventh dose, were 3-5-79-2 mg/1 (mean 24-6 ± 28-5 mg/1), and 5-0-19-6 mg/1 (mean 10-1 ±7-0 mg/1) respectively. The mean concentrations in the common bile duct bile, gallbladder bile and gallbladder wall were respectively, 3-9, 9-5 and 2-0 times higher than simultaneous serum concentrations. Maruyama et al. (1985) determined the concentrations of ofloxacin in bile in a group of eight patients treated with ofloxacin 200 mg bd. Biliary concentrations increased with time and then reached a plateau. The peak ofloxacin concentration in bile was approximately 9 mg/148 h after administration. The same authors also found that gallbladder tissue concentrations after repeated 200 mg doses were 5-36 ±0-68 mg/kg, and levels in gallbladder bile were 2-65-36-58 mg/1. Ofloxacin accumulated in bile after multiple dosing. Single dose. Maruyama et al. (1985) also determined the concentrations of ofloxacin in bile following a single dose. Two hours after a 500 mg dose the biliary ofloxacin level was 10 mg/1. Levels of the glucuronide-conjugated metabolite ranged from 10% to 28% of the total ofloxacin excreted into the bile. After a single 200 mg dose, gallbladder tissue levels were 2-3 mg/kg, and levels in gallbladder bile were 2-57 mg/1. Duben et al. (1986) measured ofloxacin levels in gallbladder bile and wall following a single 400 mg oral preoperative dose. Mean concentrations in the bile were 11-85 ±4-7 mg/1. In samples of gallbladder wall and liver tissue, the mean levels were: 4-59 ±2-72 mg/kg and 4-59 ±3-46 mg/kg respectively. Brattstrom, Malmborg & Tyden (1988) investigated the penetration of ofloxacin into the pancreatic secretions of seven patients who underwent pancreatic transplantation. Ofloxacin concentrations in pancreatic secretions were 92% of that in the serum with a mean peak level of 2-7 ±0-7 mg/1 3-6 h after drug administration. The fall in concentration with time was parallel to the decrease in serum concentration. Pederzoli et al. (1989) measured biliary ofloxacin concentrations in six patients

50 R. Lang et al undergoing biliary surgery, and concentrations in pancreatic secretions in five patients undergoing pancreatic surgery. All patients were given a single dose of 300 mg ofloxacin. Ofloxacin levels in bile were significantly higher than simultaneous serum concentrations. Peak levels were 7-8 mg/1 at 2 h. Concentrations in pancreatic secretions were generally lower than simultaneous serum levels. Maximum concentrations in the pancreatic secretions were 2 mg/1 at 2-3 h. Friess et al. (1989) analysed pancreatic tissue from patients undergoing surgery. The ofloxacin concentration following a 200 mg dose was 1-4 mg/kg. Selectivity of got decontamination by ofloxacin Van-Saene et al. (1988) studied selective gut decontamination by ofloxacin and ciprofloxacin. The impact on the indigenous flora was studied by measurement of /?- aspartoglycine content, yeast overgrowth and decrease in number of enterococci. Their results show that suppression of the faecal flora by ofloxacin and ciprofloxacin is more or less selective, although yeast overgrowth and a decrease in numbers of enterococci were more prominent with ciprofloxacin. Kern et al. (1987) studied selective decontamination in 40 granulocytopenic patients given ofloxacin in combination with amphotericin B suspension for 14-81 days (mean 35 days). Enterobacteriaceae were completely eliminated within one week. The aerobic Gramrpositive cocci and the anaerobic microorganisms were only slightly affected by ofloxacin. Clinical data Ofloxacin in the management of gastrointestinal infections shigellosis Akalin et al. (1988) treated 21 patients with acute shigellosis with two different regimens. One group (seven patients) was treated by ofloxacin 200 mg given three times in one day. The following 14 patients received 400 mg of ofloxacin as a single dose. Clinical response in the first group was rapid and occurred in all patients by day 3 (and in most patients by day 2). Stool cultures became negative for shigellae by day 2 in all patients, and by day 1 in six cases. In the second (single dose) group 13/14 responded clinically by day 2. Twelve patients had negative stools on day 1, and 13 by day 2. In one patient the stools became negative only on day 7, despite prompt clinical recovery by day 3. The conclusion from this paper is that either mode of administration of ofloxacin is highly effective in the treatment of acute shigellosis. Our data from Israel (unpublished observations) document cure of acute shigellosis in 16 patients treated by ofloxacin 400 mg given once daily for five days. All cases were clinically and bacteriologically cured by day 3. An additional ten patients with acute salmonella enteritis were also cured by day 3 or 4 with once daily ofloxacin. Tanphaichitra, Saphaphong & Srimuang (1986) and Lo (1988) demonstrated the efficacy of ofloxacin in the management of typhoid fever and there was no subsequent chronic carriage of the pathogen. In one patient described by Loffler & Westphalen (1986) chronic excretion of non-typhoidal salmonellae that had lasted for three years was terminated by therapy with ofloxacin after many other antibiotics had failed. Our data (unpublished observations) show that three of five chronic salmonella carriers became negative following one week of therapy with once daily oral ofloxacin, while the remaining two patients became negative within two weeks. Tigaud et al. (1988) reported the treatment of 21 patients with various enteric

Ofloxadn and tbe gat 51 pathogens with ofloxacin 200 mg bd for six to 30 days. One group of patients comprised 11 patients with acute enterocolitis without bacteraemia, six patients with shigellosis and five with salmonellosis. In another group of ten patients, bacteraemia with Salmonella spp. was documented in nine patients and one patient had cholelithiasis with chronic Salm. typhi carriage. All patients recovered without prolonged carriage of the pathogen. Fever lysis occurred in one to six days in the first group with eradication of the pathogen by the third day. For patients with typhoid fever, the temperature settled in two to six days; blood cultures were negative by the first day of therapy, stool cultures were negative in one to six days. Discussion Therapeutic regimens in infectious diseases are often based on traditional clinical concepts. The prolonged intravenous therapy of endocarditis and osteomyelitis are two examples of time-honoured concepts that have been recently challenged because of microbiological and pharmacological data that are supported by initial clinical observations. We have tried in this review to cast light on the scientific basis for the use of ofloxacin in the management of gastrointestinal bacterial infections. We suggest a rational approach which stems from the microbiological and pharmacological data. Inagaki et al. (1989) studied the effect of ofloxacin and its optic S-(-) isomer against various pathogens associated with bacterial diarrhoea. Both compounds were effective against enteropathogenic Esch. coli, Salmonella spp., Shigella spp., Campylobacter jejuni and Vibrio parahaemolyticus. Pharmacological data (Pecquet et al., 1987; Leigh et al., 1988) demonstrate very high faecal ofloxacin levels after four days of therapy and high faecal levels were sustained for up to five days after discontinuation of therapy. Penetration of ofloxacin to sites important for the eradication of invasive bacterial pathogens, such as gallbladder tissue, bile, pancreatic fluid (Marayuma et al., 1985; Kazmierczak et al., 1987) and mesenteric lymph nodes (Stahl et al., 1988), is above the MIC of most enteropathogens. Data from other quinolones document adequate penetration into the colonic wall also. Microbiological data concerning the effect of ofloxacin on the gastrointestinal flora are abundant and reproducible. Chida et al. (1984), Kern et al. (1987), Pecquet et al. (1987), Shah et al. (1987), Leigh et al. (1988) and Van-Saene et al. (1988), all showed that repeated doses of ofloxacin cause a complete and prolonged suppression of the normal Gram-negative enteric flora without significant effects on the anaerobic and streptococcal flora. Furthermore, and relevant to this review, Edlund et al. (1988) showed that a single dose of 400 mg ofloxacin eliminated Enterobacteriaceae within two days in most patients. On the basis of these data it is reasonable to assume that elimination of enteric bacterial pathogens will follow the pattern observed for the normal Gram-negative flora, following even a single dose of 400 mg of ofloxacin. These data are further supported by initial clinical experience. A single daily dose of ofloxacin was effective in 39 patients with bacterial diarrhoea, caused by a variety of strains. In all cases symptomatology was shortened to 72 h and recovery was prompt, with no side effects observed. However, clinical data by Akalin et al. (1988) are even more impressive and indicate a good clinical response in acute shigellosis with a oneday therapeutic regimen of 400 mg ofloxacin. The clinical response occurred within 36-48 h following initiation of therapy and did not differ from the response observed

52 R. Laaget al with more conventional therapy. Microbiological eradication was similar to that observed with traditional prolonged therapeutic regimens. We believe that the data concerning ofloxacin and the gastrointestinal tract call for a controlled clinical trial comparing a single dose of 400 mg ofloxacin with other effective regimens for enteric bacterial infections. If our hypothesis is correct, the single dose regimen is expected to be as effective as others clinically. The attractions of single dose therapy with ofloxacin for the management of bacterial diarrhoea are lower costs and better compliance, especially important in developing countries. References Akalin, H. E., Mehmet, F., Unal, S., Serin, A. & Baykal, M. (1989). Clinical efficacy of single dose or once a day treatment with ofloxacin in shigellosis. Reviews of Infectious Diseases 2, Suppl.S, 1152-3. Bayerdorffer, E., Simon, T. H., Bastlein, C. H., Ottenjann, R. & Kaspcr, G. (1987). Bismuth/ ofloxacin combination for duodenal ulcer. Lancet, ii, 1467-8. Brattstrom, C, Malmborg, A. S. & Tyden, G. (1988). Penetration of ciprofloxacin and ofloxacin into human allograft pancreatic juice. Journal of Antimicrobial Chemotherapy 22, 213-9. Chida, T., Shibaoka, H., Ishizuka, I. & Nakaya, R. (1984). The effect of ofloxacin (DL8280), a new antibacterial agent of the pyridone-carboxylic acid derivative, on human fecal flora. Chemotherapy 32, 109-17. Duben, W., Student, A., Jablonski, M. & Malottke, R. (1986). Zur Gewcbekonzentration und Wirksamkeit von Ofloxacin bei chirurgischen Patienten. Infection 14, Suppl. I, 70-2. Edlund, C, Kager, L., Malmborg, A. S. & Sjostedt, C. E. (1988). Effect of ofloxacin on oral and gastrointestinal microflora in patients undergoing gastric surgery. European Journal of Microbiology and Infectious Diseases 17, 135-43. Edlund, C, Lindqvist, L. & Nord, C. E. (1988). Norfloxacin binds to human fecal material. Antimicrobial Agents and Chemotherapy 32, 1869-74. Friess, H., Buchler, M., Malfertheiner, P., Isenman, R., Sclegel, P. & Beger, H. G. (1989). Concentrations of different bactericidal antibiotics in human pancreatic tissue. Digestion 43, 143-4. Inagaki, Y., Horiuchi, S., Une, T. & Nakaya, R. (1989). In vitro activity of DR-3355, an optically active isomer of ofloxacin, against bacterial pathogens associated with travellers' diarrhoea. Journal of Antimicrobial Chemotherapy 24, 547-9. Kazmierczak, A., Pechinot, A., Duez, J. M., Haas, O. & Favre, J. M. (1987). The biliary tract excretion of ofloxacin in man. Drugs 34, Suppl. 1, 39-43. Kern, W., Kurrl, E. & Vanek, E. (1987). Ofloxacin for prevention of bacterial infections in granulocytopenic patients. Infection 15, 427-32. Leigh, D. A., Walsh, B., Harris, K., Hancock, P. & Travers, G. (1988). Pharmacokinetics of ofloxacin and the effect on the faecal flora of healthy volunteers. Journal of Antimicrobial Chemotherapy 22, Suppl. C, 115-25. Lo, W. L. (1988). Ofloxacin in the treatment of enteric fever: a preliminary study. Journal of Antimicrobial Chemotherapy 5, 681-2. Loffler, A. & Westphalen, H. G. (1986). Successful treatment of chronic salmonella excretor with ofloxacin. Lancet i. 1206. Maruyama, K., Tanimura, H., Kobayashi, N., Mukaihara, S. & Saito, T. (1985). Efficacy of ofloxacin on biliary tract infections compared with other drugs. In Recent Advances in Chemotherapy. Proceedings of the 14th International Congress of Chemotherapy, Kyoto, 1985. Pecquet, S., Andermont, A. & Tancrede C. (1987). The effect of ofloxacin on fecal bacteria in human volunteers. Antimicrobial Agents and Chemotherapy 31, 124-5. Pederzoli, P., Falconi, M., Bassi, C, Girclli, R., Vesentini, S., Martini, N. el al. (1989). Ofloxacin penetration into bile and pancreatic juice. Journal of Antimicrobial Chemotherapy 23, 805-7. Reeves D. S. (1986). The effect of quinolone antibacterialj on the gastointcstinal flora compared with that of other antibacterials. Journal of Antimicrobial Chemotherapy 18, Suppl. D, 89-102.

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