Zbl. Bakt. 277, 273-275 (1992) © Gustav Fischer Verlag, StuttgartlNew York
Editorial
Fluoroquinolones and Bacterial Enteric Infections S. RAGNAR NORRByl and JOHAN WISTROM 2 Department of Infectious Diseases, University of Lund, Lund University Hospital, 22185 Lund, Sweden 2 Department of Infectious Diseases, University of Umea, Umea, Sweden 1
The introduction in the 1980ies of new fluoroquinolones such as norfloxacin, ciprofloxacin and ofloxacin offered a new therapeutic alternative for antibiotic intervention in bacterial enteric infections. The antibacterial spectrum of these compounds generally includes Salmonella spp., Shigella spp., Vibrio cholerae, Vibrio parahaemolyticus, Campylobaeter spp., enterotoxigenic Escherichia coli, Aeromonas spp. and Plesiomonas, spp., that is, all major bacterial species implicated as causative agents of bacterial enteritis (12). Another factor of importance was that many of the quinolones achieve high concentrations in the faecal content and markedly reduce or even eliminate the Gram-negative aerobic flora during treatment (6). These findings initiated clinical trials in both treatment and prevention of enteric infections.
Prophylaxis Against Travellers' Diarrhoea The efficacy of fluoroquinolones in prevention of travellers' diarrhoea has been studied in several double-blind placebo-controlled trials (11,12). They demonstrated that prophylaxis markedly reduced the incidence of diarrhoea, especially severe infections. This effect was seen in travellers going to high risk countries like those in Africa, Southeast Asia and Latin America. Travellers going to countries with lower risks of acquiring enteritis, for example Greece, Spain, Portugal and the Canary Islands, showed minor benefits from quinolone prophylaxis. The frequencies of adverse reactions to the quinolones were low in these trials and, importantly, with the derivatives studied only very few cases of photosensitization have been reported in prophylactic trials. The negative ecological effects in terms of alterations of the faecal flora and selection of resistant bacterial strains were minimal and far less than previously reported with other 8gents such as co-trimoxazole, doxycycline and mecillinam. It is easy to take these results and state that prophylaxis should be used by travellers to high risk countries. However, with increasing tourism to exotic countries, this would result in an enormous consumption of fluoroquinolones. The consequences of such use, even if the economical aspects are disregarded, have not been evaluated. The current recommendation is to limit the prophylactic use to short-term (:s 4 weeks) travellers who have underlying diseases which would increase the risks of serious medical consequences of an enteritis. Such
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diseases are insulin treated diabetes mellitus, unstable cardiac decompensation, reactive arthritis, gastric achylia, chronic inflammatory bowel disease and immune deficiencies. In those patients we recommend that prophylaxis is given to persons who travel to high risk countries for not more than four weeks. In other travellers, prophylaxis should be used restrictively. Short-Term Self-Treatment of Travellers' Diarrhoea As a consequence of the obvious need to limit the use of prophylactic f1uoroquinolones in travellers, studies have been undertaken in which the subjects were instructed to start treatment with a quinolone or placebo as soon as possible (within 24 hours) after onset of symptoms of enteritis (4, 8, 9). Again clear benefits were demonstrated. For example, norfloxacin 400 mg twice daily for three days significantly reduced the number of loose stools and the time to recovery when compared to placebo (9). Also in these studies, the adverse reactions were minor. In one of them it could be calculated that if all travellers had taken norfloxacin prophylaxis, the number of treatment days would have been about 11000. If, on the other hand, those who developed diarrhoea had taken self-treatment only 400 treatment days would have been required. However, when we performed a self-treatment study on volunteers going to Mexico, it could be demonstrated that post-treatment some of the subjects who received ciprofloxacin had acquired ciprofloxacin resistant Gramnegative enteric bacilli in their stools (Wistrom et aI., to be published). Thus, the absence of ecological effects of quinolone treatment was not as clear as was previously thought. However, we feel that short-term self-treatment of travellers' diarrhoea with a f1uoroquinolone is an alternative to constipating drugs such as loperamide for those who travel to countries with a high risk of enteric infections. It limits the use of antibiotics to a minimum and it prevents the common and completely uncontrolled use of locally purchased anti-diarrhoeal drugs.
Treatment of Enteric Infections Small studies have indicated that fluoroquinolone are highly effective for the treatment of shigellosis, typhoid fever and also to some extent in other types of enteritis (1, 2, 7). However, other trials have shown that f1uoroquinolones had limited efficacy in eradicating Salmonella spp. (3, 5). We did a large controlled trial in which Swedish patients with diarrhoea of less than six days duration and possible bacterial aetiology were randomized to five days treatment with norfloxacin 400 mg twice daily or placebo (10). The results were generally quite disappointing. Although statistical differences favouring norfloxacin could be demonstrated for time to recovery and reduction of number of loose stools, they were of doubtful clinical importance. Shortly after treatment significantly more patients in the norf10xacin group carried Salmonella spp. than in the placebo group. In patients with the most common aetiology, Campylobaeter spp., 14/69 patients randomized to norfloxacin failed to respond clinically and in six of them resistance to norfloxacin emerged during treatment. Only in a small number of patients with shigellosis were there indications of clear clinical benefits with norfloxacin. Why then this striking difference between the efficacy of a quinolone as a prophylactic agent or as short-term self-treatment and the results when it was used as therapy? Most probably the reason is that in the former cases treatment was started before or very shortly after onset of diarrhoea while in the treatment study a mean of 2.8 days elapsed before treatment was instituted. Moreover, while Campylobaeter spp. is common in Europe, it is not as common as a cause of enteritis in travellers to high risk areas. The obvious conclusion of these results is that, similar to other antibiotics, norfloxacin, and probably also other fiuoroquinolones, seem to have a limited usefulness for routine
Fluoroquinolones and Bacterial Enteric Infections
275
empiric treatment of bacterial enteritis. We recommend that such treatment should be used mainly when shigellosis is suspected or when the patients have symptoms of systemic infections.
Conclusions The new fluoroquinolones are execellent antibiotics in many types of infections. However, in the treatment of diarrhoea they have not met with all expections. While extremely effective and safe as prophylaxIs or self-treatment of travellers' diarrhoea, they caused less than satisfactory clinical results and poor microbiological results in patients with enteric bacterial infections treated some time after onset of symptoms. The lesson to be learned from these studies is that one cannot extrapolate data from microbiological sensitivity and pharmacokinetics to clinical efficacy and not even from one type of treatment to another.
References 1. Asperilla, M. 0., R. A. Smego, and L. K. Scott: Quinolone antibiotics in the treatment of salmonella infections. Rev. Infect. Dis. 12 (1990) 873-879 2. Beenish, M. L., M. A. Salam, R. Haider, and M. Barza: Therapy for shigellosis. II. Randomized double-blind comparison of ciprofloxacin and ampicillin. J. Infect. Dis. 162 (1990) 711-716 3. Carlsted, C., P. Dahl, P.M. Niklasson, K. Cullberg, C. Banck, and C. Kahlmeter: Norfloxacin treatment of acute salmonellosis does not shorten the carriage state. Scand. J. Infect. Dis 22 (1990) 553-557 4. Ericsson, CD., P.C Johnson, H.L. DuPont, D.R. Morgan, ].A.N. Bitsura, and F.]. De la Cabada: Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers' diarrhea. A placebo-controlled randomized trial. Ann. Intern. Med. 106 (1987) 216-220 5. Neill, M. A., S. M. Opal, ]. Heelan, R. Cuisti,]. E. Cassidy, and K. H. Mayer: Failure of ciprofloxacin to eradicate convalescent fecal excretion after acute salmonellosis: Experience during an outhbreak in health care workers. Ann. Intern. Med. 114 (1991) 195-199 6. Nord, CE.: Effect of the new quinolones on the human gastrointestinal microflora. Rev. Infect. Dis. 10, Supp!. 1 (1987) S193-196 7. Pichler, H., C. Diridl, K. Stickler, and D. Wolf: Clinical efficacy of ciprofloxacin compared to placebo in bacterial diarrhea. Am. J. Med. 82, Suppl. 4A (1987) 329-332 8. Steffen, R., R. Heusser, A. Tschopp, and H. L. DuPont: Efficacy and side effects of six agents in the self-treatment of travellers' diarrhea. Trav. Med. Int. 6 (1988) 153-157 9. Wistrom,]., M. Jertborn, s.A. Hedstrom, K. Alestig, C. Englund, B. Jellhelden, and S. R. Norrby: Short-term self-treatment of travellers' diarrhoea with norfloxacin: a placebo-controlled study. J. Antimicrob. Chemother. 23 (1989) 905-913 10. Wistrom,]., M. Jertborn, J. Wistrom, M. Jertborn, E. Ekvall, K. Norlin, B. Soderquist, L. Lagergren, C. Englund, and S. R. Norrby: Empiric treatment of acute diarrhea with norfloxacin: A placebo-controlled study in 511 patients. Ann. Intern. Med., in press 11. Wistrom,]., S. R. Norrby, L. C. Burman, R. Lundholm, B. Jellheden, and C. Englund: Norfloxacin versus placeho for prophylaXIS against travellers' diarrhoea.]. Antimicrob. Chemother. 20 (1987) 563-574 12. Wistrom, J. and S. R. Norrby: Antibiotic prophylaxis of travellers' diarrhoea. Scand. ]. Infect. Dis. Supp!. 70 (1990) 111-129 Dr. S. Ragnar Norrby, Dept. of Infectious Diseases, University of Lund, Lund University Hospital, S-22185 Lund, Sweden
Editorial
Fluoroquinolones and Bacterial Enteric Infections S. RAGNAR NORRByl and JOHAN WISTROM 2 Department of Infectious Diseases, University of Lund, Lund University Hospital, 22185 Lund, Sweden 2 Department of Infectious Diseases, University of Umea, Umea, Sweden 1
The introduction in the 1980ies of new fluoroquinolones such as norfloxacin, ciprofloxacin and ofloxacin offered a new therapeutic alternative for antibiotic intervention in bacterial enteric infections. The antibacterial spectrum of these compounds generally includes Salmonella spp., Shigella spp., Vibrio cholerae, Vibrio parahaemolyticus, Campylobaeter spp., enterotoxigenic Escherichia coli, Aeromonas spp. and Plesiomonas, spp., that is, all major bacterial species implicated as causative agents of bacterial enteritis (12). Another factor of importance was that many of the quinolones achieve high concentrations in the faecal content and markedly reduce or even eliminate the Gram-negative aerobic flora during treatment (6). These findings initiated clinical trials in both treatment and prevention of enteric infections.
Prophylaxis Against Travellers' Diarrhoea The efficacy of fluoroquinolones in prevention of travellers' diarrhoea has been studied in several double-blind placebo-controlled trials (11,12). They demonstrated that prophylaxis markedly reduced the incidence of diarrhoea, especially severe infections. This effect was seen in travellers going to high risk countries like those in Africa, Southeast Asia and Latin America. Travellers going to countries with lower risks of acquiring enteritis, for example Greece, Spain, Portugal and the Canary Islands, showed minor benefits from quinolone prophylaxis. The frequencies of adverse reactions to the quinolones were low in these trials and, importantly, with the derivatives studied only very few cases of photosensitization have been reported in prophylactic trials. The negative ecological effects in terms of alterations of the faecal flora and selection of resistant bacterial strains were minimal and far less than previously reported with other 8gents such as co-trimoxazole, doxycycline and mecillinam. It is easy to take these results and state that prophylaxis should be used by travellers to high risk countries. However, with increasing tourism to exotic countries, this would result in an enormous consumption of fluoroquinolones. The consequences of such use, even if the economical aspects are disregarded, have not been evaluated. The current recommendation is to limit the prophylactic use to short-term (:s 4 weeks) travellers who have underlying diseases which would increase the risks of serious medical consequences of an enteritis. Such
274
S. R. Norrby and J. Wistrom
diseases are insulin treated diabetes mellitus, unstable cardiac decompensation, reactive arthritis, gastric achylia, chronic inflammatory bowel disease and immune deficiencies. In those patients we recommend that prophylaxis is given to persons who travel to high risk countries for not more than four weeks. In other travellers, prophylaxis should be used restrictively. Short-Term Self-Treatment of Travellers' Diarrhoea As a consequence of the obvious need to limit the use of prophylactic f1uoroquinolones in travellers, studies have been undertaken in which the subjects were instructed to start treatment with a quinolone or placebo as soon as possible (within 24 hours) after onset of symptoms of enteritis (4, 8, 9). Again clear benefits were demonstrated. For example, norfloxacin 400 mg twice daily for three days significantly reduced the number of loose stools and the time to recovery when compared to placebo (9). Also in these studies, the adverse reactions were minor. In one of them it could be calculated that if all travellers had taken norfloxacin prophylaxis, the number of treatment days would have been about 11000. If, on the other hand, those who developed diarrhoea had taken self-treatment only 400 treatment days would have been required. However, when we performed a self-treatment study on volunteers going to Mexico, it could be demonstrated that post-treatment some of the subjects who received ciprofloxacin had acquired ciprofloxacin resistant Gramnegative enteric bacilli in their stools (Wistrom et aI., to be published). Thus, the absence of ecological effects of quinolone treatment was not as clear as was previously thought. However, we feel that short-term self-treatment of travellers' diarrhoea with a f1uoroquinolone is an alternative to constipating drugs such as loperamide for those who travel to countries with a high risk of enteric infections. It limits the use of antibiotics to a minimum and it prevents the common and completely uncontrolled use of locally purchased anti-diarrhoeal drugs.
Treatment of Enteric Infections Small studies have indicated that fluoroquinolone are highly effective for the treatment of shigellosis, typhoid fever and also to some extent in other types of enteritis (1, 2, 7). However, other trials have shown that f1uoroquinolones had limited efficacy in eradicating Salmonella spp. (3, 5). We did a large controlled trial in which Swedish patients with diarrhoea of less than six days duration and possible bacterial aetiology were randomized to five days treatment with norfloxacin 400 mg twice daily or placebo (10). The results were generally quite disappointing. Although statistical differences favouring norfloxacin could be demonstrated for time to recovery and reduction of number of loose stools, they were of doubtful clinical importance. Shortly after treatment significantly more patients in the norf10xacin group carried Salmonella spp. than in the placebo group. In patients with the most common aetiology, Campylobaeter spp., 14/69 patients randomized to norfloxacin failed to respond clinically and in six of them resistance to norfloxacin emerged during treatment. Only in a small number of patients with shigellosis were there indications of clear clinical benefits with norfloxacin. Why then this striking difference between the efficacy of a quinolone as a prophylactic agent or as short-term self-treatment and the results when it was used as therapy? Most probably the reason is that in the former cases treatment was started before or very shortly after onset of diarrhoea while in the treatment study a mean of 2.8 days elapsed before treatment was instituted. Moreover, while Campylobaeter spp. is common in Europe, it is not as common as a cause of enteritis in travellers to high risk areas. The obvious conclusion of these results is that, similar to other antibiotics, norfloxacin, and probably also other fiuoroquinolones, seem to have a limited usefulness for routine
Fluoroquinolones and Bacterial Enteric Infections
275
empiric treatment of bacterial enteritis. We recommend that such treatment should be used mainly when shigellosis is suspected or when the patients have symptoms of systemic infections.
Conclusions The new fluoroquinolones are execellent antibiotics in many types of infections. However, in the treatment of diarrhoea they have not met with all expections. While extremely effective and safe as prophylaxIs or self-treatment of travellers' diarrhoea, they caused less than satisfactory clinical results and poor microbiological results in patients with enteric bacterial infections treated some time after onset of symptoms. The lesson to be learned from these studies is that one cannot extrapolate data from microbiological sensitivity and pharmacokinetics to clinical efficacy and not even from one type of treatment to another.
References 1. Asperilla, M. 0., R. A. Smego, and L. K. Scott: Quinolone antibiotics in the treatment of salmonella infections. Rev. Infect. Dis. 12 (1990) 873-879 2. Beenish, M. L., M. A. Salam, R. Haider, and M. Barza: Therapy for shigellosis. II. Randomized double-blind comparison of ciprofloxacin and ampicillin. J. Infect. Dis. 162 (1990) 711-716 3. Carlsted, C., P. Dahl, P.M. Niklasson, K. Cullberg, C. Banck, and C. Kahlmeter: Norfloxacin treatment of acute salmonellosis does not shorten the carriage state. Scand. J. Infect. Dis 22 (1990) 553-557 4. Ericsson, CD., P.C Johnson, H.L. DuPont, D.R. Morgan, ].A.N. Bitsura, and F.]. De la Cabada: Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers' diarrhea. A placebo-controlled randomized trial. Ann. Intern. Med. 106 (1987) 216-220 5. Neill, M. A., S. M. Opal, ]. Heelan, R. Cuisti,]. E. Cassidy, and K. H. Mayer: Failure of ciprofloxacin to eradicate convalescent fecal excretion after acute salmonellosis: Experience during an outhbreak in health care workers. Ann. Intern. Med. 114 (1991) 195-199 6. Nord, CE.: Effect of the new quinolones on the human gastrointestinal microflora. Rev. Infect. Dis. 10, Supp!. 1 (1987) S193-196 7. Pichler, H., C. Diridl, K. Stickler, and D. Wolf: Clinical efficacy of ciprofloxacin compared to placebo in bacterial diarrhea. Am. J. Med. 82, Suppl. 4A (1987) 329-332 8. Steffen, R., R. Heusser, A. Tschopp, and H. L. DuPont: Efficacy and side effects of six agents in the self-treatment of travellers' diarrhea. Trav. Med. Int. 6 (1988) 153-157 9. Wistrom,]., M. Jertborn, s.A. Hedstrom, K. Alestig, C. Englund, B. Jellhelden, and S. R. Norrby: Short-term self-treatment of travellers' diarrhoea with norfloxacin: a placebo-controlled study. J. Antimicrob. Chemother. 23 (1989) 905-913 10. Wistrom,]., M. Jertborn, J. Wistrom, M. Jertborn, E. Ekvall, K. Norlin, B. Soderquist, L. Lagergren, C. Englund, and S. R. Norrby: Empiric treatment of acute diarrhea with norfloxacin: A placebo-controlled study in 511 patients. Ann. Intern. Med., in press 11. Wistrom,]., S. R. Norrby, L. C. Burman, R. Lundholm, B. Jellheden, and C. Englund: Norfloxacin versus placeho for prophylaXIS against travellers' diarrhoea.]. Antimicrob. Chemother. 20 (1987) 563-574 12. Wistrom, J. and S. R. Norrby: Antibiotic prophylaxis of travellers' diarrhoea. Scand. ]. Infect. Dis. Supp!. 70 (1990) 111-129 Dr. S. Ragnar Norrby, Dept. of Infectious Diseases, University of Lund, Lund University Hospital, S-22185 Lund, Sweden
