Eradication of non-typhoid salmonellae in acute enteritis after therapy with ofloxacin for 5 or 10 days

Pål Voltersvika,*, Alfred Halstensenb, Nina Langelandb, Asbjørn Digranesc, Lars Erik Petersond, Tore Rolstade and Claus Ola Solbergb

a Department of Infectious Diseases Prevention, City of Bergen; b Institute of Medicine and c Department of Microbiology and Immunology, The Gade Institute, University of Bergen, Bergen, Norway; d Department of Statistics, University of Gøteborg, Gothenburg, Sweden; e Hoechst Marion Roussel, Oslo, Norway


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Eradication of non-typhoid salmonellae was evaluated in a randomized, double-blinded study of 49 patients with acute enteritis after therapy with ofloxacin 400 mg once daily for 5 or 10 days. Early eradication of salmonellae was found in 57% of patients in the 5 day therapy group and in 74% of patients in the 10 day therapy group. This difference was larger among severely ill patients. Together with our previous study of ofloxacin therapy for 3 days or placebo, this shows that early eradication of non-typhoid salmonellae increases with duration of ofloxacin therapy without an increase in persistence of salmonellae in stools or development of resistant strains.


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Antimicrobial therapy of acute bacterial enteritis remains controversial.1 Although they have high activity against enteropathogenic bacteria in vitro, a number of antimicrobial agents have little or no effect on eradication in vivo.2,3 The quinolones, with high activity and favourable bioavailability, may offer a better opportunity for treatment of acute bacterial enteritis.4 The clinical efficacy of these agents in acute salmonella enteritis has been demonstrated in placebo-controlled studies,5,6 but bacteriological efficacy has been disappointing.5 Prolonged persistence of non-typhoid salmonellae in stools after quinolone therapy has been reported.7

In an earlier study,5 39 patients with acute salmonella enteritis were randomized to receive either the quinolone ofloxacin 400 mg od for 3 days or placebo. The ofloxacin group showed clinical improvement earlier than the placebo group, but at the end of therapy the eradication of salmonellae from stools was similar in the two groups. The aim of the present study was to examine the effect of ofloxacin 400 mg od for 5 or 10 days on eradication of non-typhoid salmonellae.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Patients

The recorded clinical history included age and gender, country of salmonella acquisition, duration of illness, maximum body temperature, presence of shivering, maximum number of loose stools per day, blood in stools and abdominal pain during the illness. The study was approved by the Regional Committee for Ethics in Medical Research; informed consent was given by all patients before therapy.

Inclusion and exclusion criteria

Patients aged >=18 years with acute enteritis and three or more unformed stools per day on inclusion were recruited. Forty-nine patients with non-typhoid salmonellae isolated from stools were included for ofloxacin therapy, follow-up and final evaluation. During the week before inclusion they had received no antimicrobial therapy. None of the patients recruited had to be excluded from the study because of lack of follow-up, contraindication of quinolones or other medical reasons.

Study design

Thirty and 19 patients were randomized, double blinded, to 400 mg ofloxacin od for 5 days (ofloxacin for 5 days followed by placebo for 5 days) or 10 days, respectively. Stool samples were collected at the beginning of therapy, on days 7, 12, 19, 26 and 40 (all ±1 day) after initiation of therapy and weekly thereafter until salmonellae were absent from three subsequent samples. Except for two missing samples in the 5 day therapy group, all samples were available for culture. The patients received no other antimicrobial therapy during the follow-up period.

Bacteriological studies

Salmonella isolates were identified by routine bacteriological methods and serotyped using antisera from Behring Diagnostics, Frankfurt, Germany. Susceptibility to ofloxacin was determined by the Etest (AB Biodisk, Solna, Sweden).8 Isolates with MICs of <=0.5 mg/L were recorded as susceptible, those with MICs between >0.5 and <8.0 mg/L as intermediate and those with MICs of >=8.0 mg/L as resistant.9

Evaluation criteria

The outcome was defined as ‘early eradication’ when no salmonellae were isolated from stool samples at the end of therapy or at subsequent follow-up examinations. The outcome was defined as ‘failure’ if salmonellae were found in stools at the end of therapy or at subsequent follow-up examinations.

Statistical analysis

Fisher's exact test (two-tailed) was applied for statistical analysis; P values <=0.05 were regarded as significant.


    Results and discussion
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
The age of the 49 included patients ranged from 20 to 75 years. None of them suffered diseases other than acute enteritis. Thirty-three (67%) patients had acquired infection in Mediterranean countries and only two (4%) in Norway. The distribution of age and gender and the severity of symptoms before therapy were similar in the 5 and 10 days' therapy groups. The mean duration of diarrhoea before therapy was 13 and 15 days in the 5 and 10 day therapy groups, respectively.

In our earlier study, early eradication of non-typhoid salmonellae was as low as 14% and 18% in patients receiving placebo or ofloxacin 400 mg od, respectively, for 3 days.5 In the present study, early bacteriological eradication was recorded in 31 (63%) of the patients. Extending ofloxacin therapy from 5 to 10 days increased early salmonella eradication from 57% (17/30) to 74% (14/19) (P = 0.16) (TableGo). The proportion of salmonella stool carriers was always lower in the 10 day therapy group (FigureGo). This was particularly notable on days 18–20, when 43% (13/30) of patients in the 5 day therapy group and only 11% (2/19) in the 10 day therapy group were carriers (P = 0.04). These results contrast with those from other studies of patients with acute salmonella enteritis, where quinolone therapy either delayed eradication or failed to eradicate salmonella in stools.4,7


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Table. Eradication of non-typhoid salmonellae related to duration of ofloxacin therapy and pretherapy symptoms, and persistence of salmonellae at 6 weeks
 


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Figure. Proportion of patients with non-typhoid salmonellae in stools at follow-up. ({blacksquare}, 5 days of ofloxacin treatment; {square}, 10 days of ofloxacin treatment).

 
Salmonella enteritidis was isolated in 27 (55%) of the 49 patients. Irrespective of duration of therapy and susceptibility of the initial isolates, S. enteritidis seemed more difficult to eradicate than other salmonella serotypes, but this difference was not significant (P = 0.08 ) (TableGo). Extending therapy from 5 to 10 days increased the eradication of S. enteritidis from 47% (9/19) to 63% (5/8) (P = 0.68), and increased the eradication of other salmonella serotypes from 73% (8/11) to 82% (9/11) (P = 1.0).

Thirty-nine (80%) patients had fever >38.0°C, 33 (67%) had severe diarrhoea (>10 stools/day) and 31 (63%) had abdominal pain. In the patients with abdominal pain, early eradication of salmonella was achieved in 45% (9/20) and 91% (10/11) of those treated for 5 and 10 days, respectively (P = 0.02). Patients with >=10 stools per day experienced 45% (9/20) and 83% (10/12) eradication when treated for 5 and 10 days, respectively (P = 0.06) (TableGo).

The main reasons for clinicians not initiating antimicrobial therapy in acute salmonella enteritis have been: the low clinical and bacteriological efficacy; the prolongation of salmonella carriage after therapy;7 and the fear of development of drug resistance.10 In our study, the persistence of salmonella isolated from stools 6 weeks after the start of therapy was not significantly different between the groups: 18% (5/28) in the 5 day therapy group and 11% (2/19) in the 10 day therapy group (P = 0.68). All these patients were followed weekly until three subsequent negative cultures were obtained, the last one being 18 weeks after the start of therapy.

All but two strains isolated before, during and after therapy were fully susceptible to ofloxacin. These two strains were intermediately susceptible; one isolate with intermediate susceptibility was eradicated at the end of therapy. The other strain persisted; the MIC of this isolate was 1.0 mg/L initially and 6.0 mg/L after 5 days of therapy; four subsequent isolates had MICs of 0.75–1.5 mg/L. Except for this, the susceptibility of isolates after therapy was the same as that before therapy in both therapy groups. S. enteritidis had susceptibility patterns similar to those of the other salmonella strains. Resistance of salmonella to quinolones can develop during treatment. Therefore, we recommend that every post-therapy isolate should be monitored for changes in MIC. Salmonella typhimurium DT104, which is often resistant to quinolones, was not observed in the present study.

Although acute salmonella enteritis may, for some patients, cause great inconvenience and disability, it is usually a self-limiting disease in otherwise healthy individuals, and the use of antimicrobial therapy is controversial. Accordingly, such therapy should be based on age, presence of underlying diseases, severity of clinical symptoms and the objective of therapy: whether to avoid serious complications of infection (septicaemia or even death), to achieve early relief of clinical symptoms or to shorten shedding and spread of salmonella.1 Our previous study5 and the present one demonstrate that early eradication of non-typhoid salmonellae increases with duration of ofloxacin therapy without a concomitant increase in the persistence of salmonellae in stools or development of resistant strains. Severely ill patients seem to benefit more from 10 days of ofloxacin therapy than from 5 days of therapy.


    Acknowledgments
 
This study was supported by Aventis Pharma.


    Notes
 
* Correspondence address. Centre for Research in Virology, Department of Microbiology and Immunology, The Gade Institute, University of Bergen, PO Box 7800, N-5020 Bergen, Norway. Tel: +47-55584510; Fax: +47-55584512; E-mail: pal.voltersvik{at}vir.uib.no Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
1 . DuPont, H. L. (1997). Guidelines on acute infectious diarrhea in adults. The Practice Parameter Committee of the American College of Gastroenterology. American Journal of Gastroenterology 92, 1962–75.[ISI][Medline]

2 . Carlstedt, G., Dahl, P., Niklasson, P. M., Gullberg, K., Banck, G. & Kahlmeter, G. (1990). Norfloxacin treatment of salmonellosis does not shorten the carrier stage. Scandinavian Journal of Infectious Diseases 22, 553–6.[ISI][Medline]

3 . Pichler, H. E., Diridl, G., Stickler, K. & Wolf, D. (1987). Clinical efficacy of ciprofloxacin compared with placebo in bacterial diarrhea. American Journal of Medicine 82, 329–32.[ISI][Medline]

4 . Hof, H. & Kretschmar, M. (1994). Rational therapy of salmonella enteritis. Leber Magen Darm 24, 57–64.[ISI][Medline]

5 . Halstensen, A., Voltersvik, P., Gossius, G., Digranes, A., Peterson, L. E., Rolstad, T. et al. (1995). Double-blind comparison of ofloxacin for 3 days and placebo in acute bacterial enteritis. Drugs 49, Suppl. 2, 454–6.[Medline]

6 . Sánchez, C., García-Restoy, E., Garau, J., Bella, F., Freixas, N., Simó, M. et al. (1993). Ciprofloxacin and trimethoprim–sulfamethoxazole versus placebo in acute uncomplicated Salmonella enteritis: a double-blind trial. Journal of Infectious Diseases 168, 1304–7.[ISI][Medline]

7 . Akalin, H. E. (1995). Role of quinolones in the treatment of diarrhoeal diseases. Drugs 49, Suppl. 2, 128–31.[Medline]

8 . Sánchez, M. L. & Jones, R. N. (1993). E-test, an antimicrobial susceptibility testing method with broad clinical and epidemiological application. Antimicrobic Newsletter 8, 1–8.

9 . Bergan, T., Bruun, J. N., Digranes, A., Lingaas, E., Melby, K. K. & Sander, J. (1967). Susceptibility testing of bacteria and fungi. Report from the Norwegian Working Group on Antibiotics. Scandinavian Journal of Infectious Diseases 103, Suppl. 17, 1–36.

10 . Piddock, L. J., Whale, K. & Wise, R. (1990). Quinolone resistance in salmonella: clinical experience. Lancet 335, 1459.[ISI][Medline]

Received 22 November 1999; returned 29 February 2000; revised 18 April 2000; accepted 22 May 2000





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