Journal of Antimicrobial Chemotherapy (2000) 46, Suppl. S1, 41–48
JAC
Effect on the human normal microflora of oral antibiotics for treatment of urinary tract infections Charlotta Edlunda,b and Carl Erik Norda* a
Department of Microbiology, Pathology and Immunology, Huddinge University Hospital, Karolinska Institute and bSödertörns Högskola, University College, Stockholm, Sweden
Oral administration of antibiotics for treatment of urinary tract infections (UTIs) can cause ecological disturbances in the normal intestinal microflora. Poorly absorbed drugs can reach the colon in active form, suppress susceptible microorganisms and disturb the ecological balance. Suppression of the normal microflora may lead to reduced colonization resistance with subsequent overgrowth of pre-existing, naturally resistant microorganisms, such as yeasts and Clostridium difficile. New colonization by resistant potential pathogens may also occur and may spread within the body or to other patients and cause severe infections. It is therefore important to learn more about the ecological effects of antibacterial agents on the human microflora. The impact on intestinal microorganisms of oral antibiotics used for the treatment of UTIs is reviewed here. Ampicillin, amoxycillin and co-amoxiclav suppress both the aerobic and anaerobic intestinal microflora with overgrowth of ampicillin-resistant Enterobacteriaceae. Pivmecillinam also affects the intestinal microflora, suppressing Escherichia coli, but does not have a major effect on the anaerobic microflora. Several orally administered cephalosporins, such as cefixime, cefpodoxime, cefprozil and ceftibuten, reduce the number of Enterobacteriaceae and increase the number of enterococci. Colonization with C. difficile has also been observed. Fluoroquinolones eliminate or strongly suppress intestinal Enterobacteriaceae, but affect enterococci and anaerobic bacteria only slightly. When antimicrobial agents are prescribed for the treatment of UTIs, not only the antimicrobial spectrum of the agent but also the potential ecological disturbances, including the risk of emergence of resistant strains, should be considered.
the transfer of resistance genes among the same or other bacterial species.6,7 The resistant bacteria may persist for weeks or months after the end of antibiotic treatment. Several factors influence the extent to which a given antimicrobial agent will alter the normal microflora. Of these, the main factor is the degree of absorption of agents administered by mouth. Poorly absorbed drugs can reach the colon in active form where they suppress susceptible microorganisms and disturb the ecological balance. Antibacterial drugs that are secreted in the bile or from the intestinal mucosa may also affect the normal intestinal microflora. It is therefore of clinical importance to determine the ecological effects of different antibacterial agents on the human microflora. During the last decade, the effect of different agents has been studied by several investigators.
Introduction Oral administration of antibiotics for treatment of urinary tract infections (UTIs) can cause quantitative and qualitative ecological disturbances in the normal intestinal microflora. The former may lead to decreased colonization resistance with subsequent overgrowth of pre-existing, naturally resistant microorganisms, such as yeasts, which may cause systemic infections in immunocompromised patients, and Clostridium difficile, which may lead to diarrhoea and/or colitis.1–4 Qualitative alterations such as selection of resistant intestinal microorganisms and establishment of new resistant pathogenic bacteria are common side effects of antibiotic treatment.5 These microorganisms may also colonize other areas of the host or spread to other patients. Overgrowth of resistant bacteria also encourages
*Correspondence address. Department of Microbiology, Pathology and Immunology, F82, Huddinge University Hospital, SE-141 86 Stockholm, Sweden. Tel: 46-8-585-878-38; Fax: 46-8-711-3918; E-mail:
[email protected]
41 © 2000 The British Society for Antimicrobial Chemotherapy
C. Edlund and C. E. Nord Motohiro et al.16 investigated the effect of co-amoxiclav on the intestinal microflora in eight volunteers. Four persons received co-amoxiclav 187.5 mg and four 375 mg (amoxycillin:clavulanate ratio 2:1) orally for 5 days. The number of enterococci and Enterobacteriaceae increased but the number of staphylococci decreased significantly. The anaerobic microflora was not altered. In six subjects receiving amoxycillin 250 mg and clavulanate 125 mg tds for 7 days,17 the number of streptococci in the intestinal microflora decreased significantly and staphylococci were eliminated. No other alterations were observed.
The ecological effects on intestinal microflora of different oral antibiotics for the treatment of UTIs are reviewed.
Effect of oral penicillins on the microflora (Table I) Ampicillin In 10 volunteers given ampicillin 1–3 g perorally for 5 days, the number of Escherichia coli, enterococci, bifidobacteria and bacteroides in the intestinal microflora decreased significantly, whereas ampicillin-resistant Citrobacter, Klebsiella and Proteus spp. increased.8 In a study of 10 volunteers given ampicillin 0.5 g tds perorally for 5 days,9 the number of Enterobacteriaceae increased in six volunteers and overgrowth of Candida spp. was observed in two persons. Diarrhoea was noticed in five volunteers.
Pivmecillinam Sullivan et al.18 studied the intestinal microflora before, during and after administration of pivmecillinam. Fifteen volunteers were given pivmecillinam tablets 400 mg bd for 7 days. Stool specimens were taken before administration (days –3 and 0), on days 2, 4 and 7 during the administration period, and 14 and 21 days after the start of the administration. The number of E. coli decreased during the administration period and there was a slight increase in the number of Bacillus spp. No major changes were observed in the anaerobic intestinal microflora.
Amoxycillin Of eight patients with respiratory tract infections given amoxycillin 2 g per day orally for 15 days, the total number of microorganisms in the intestinal microflora increased in four patients and Candida spp. increased in three.10 In another study, the number of Enterobacteriaceae increased significantly in four of 10 volunteers given amoxycillin 250 mg tds for 5 days.9 Christensson et al.11 studied 44 patients receiving amoxycillin 250 mg tds for 7 days for lower respiratory tract infections. The numbers of Enterobacteriaceae and anaerobic bacteria in the intestinal microflora increased significantly during treatment. In 10 volunteers given amoxycillin 500 mg tds for 7 days,12 the number of streptococci, staphylococci and Gram-positive anaerobic bacilli in the intestinal microflora decreased; there was an overgrowth of Klebsiella spp. in six persons and of Enterobacter spp. in two persons.
Comments Ampicillin strongly suppresses both the aerobic and the anaerobic intestinal microflora. Amoxycillin, an acidstable derivative of ampicillin, causes only minor suppression of the normal microflora, although overgrowth of resistant enterobacteria has been observed. Co-amoxiclav causes overgrowth of resistant Enterobacteriaceae. Pivmecillinam alters the intestinal microflora, suppressing aerobic Gram-negative bacteria. These agents affect the anaerobic microflora only slightly. None of the penicillins cause any major overgrowth of C. difficile or yeasts.
Co-amoxiclav
Effect of oral cephalosporins on the microflora (Table II)
Mittermayer compared the effects of amoxycillin and coamoxiclav on the intestinal microflora.13 Six volunteers were given amoxycillin 500 mg tds perorally and six volunteers co-amoxiclav 625 mg tds perorally for 7 days. The two treatment regimens did not affect the total number of aerobic and anaerobic bacteria. The Enterobacteriaceae resistant to amoxycillin increased in both treatment groups and co-amoxiclav-resistant Enterobacteriaceae increased in the group receiving co-amoxiclav. No other significant changes in the microflora were observed. In 11 children given co-amoxiclav 27.5 mg/kg bodyweight qds for 10–11 days,14 overgrowth of resistant E. coli strains was observed and no other alterations in the microflora occurred. In another study of six people receiving amoxycillin 500 mg and clavulanate 250 mg tds for 3 days, the intestinal microflora did not change during the investigation period.15
Cefaclor In one study,19 six volunteers were given cefaclor 250 mg tds for 14 days. The aerobic intestinal microflora was not altered markedly, but bifidobacteria were eliminated in two volunteers. In 10 subjects receiving 250 mg cefaclor tds for 7 days,20 the aerobic microflora was not changed, but minor changes in the anaerobic microflora occurred. In 40 patients with lower respiratory tract infections treated with 250 mg cefaclor tds for 7 days,11 the number of enterococci, Enterobacteriaceae, bacteroides and Candida albicans in the intestinal microflora increased markedly whereas the numbers of streptococci, staphylococci and anaerobic cocci decreased during the administration of cefaclor. 42
Table I. Effect of oral penicillins on the intestinal microflora Effect on Agent
Dose (mg/day)
Ampicillin
5 5 15 5 7 7 7 7 10–11 3 5 5 7 7
10 10 8 10 44 10 6 6 11 6 4 4 6 15
– – – – – –
– – – – – – – –
– – – – – – – – – –
– – – – –
– – – – – – – – – – – – –
– – – – – – – – – – –
8 9 10 9 11 12 13 13 14 15 16 16 17 18
43
, strong suppression (4 log10 cfu/g faeces); , mild to moderate suppression (2–4 log10 cfu/g faeces); , increase in number of microorganisms during therapy; , marked increase; –, no significant change. a The amoxycillin:clavulanic acid ratio was 2:1.
Table II. Effect of oral cephalosporins on the intestinal microflora Effect on Agent Cefaclor
Cefixime Cefpodoxime proxetil Cefprozil Ceftibuten Cephradine
Dose Days of Number (mg/day) administration of patients
Overgrowth of resistant strains aerobic Gram- anaerobic enterobacteria positive cocci bacteria enterobacteria C. difficile Candida spp. Reference
250 3 250 3 250 3 400 200 2
14 7 7 14 7
6 10 40 6 10
– –
– –
– –
– – – –
– –
– – – –
19 20 11 19 21
200 2 500 2 400 1 1000 2
7 8 10 7
10 8 14 6
–
–
– – – –
– –
– –
12 22 23 17
, strong suppression (4 log10 cfu/g faeces); , mild to moderate suppression (2–4 log10 cfu/g faeces); , increase in number of microorganisms during therapy; , marked increase; –, no significant change.
Oral antibiotics and normal microflora
1000–3000 500 3 Amoxycillin 2000 250 3 250 3 500 3 500 3 Co-amoxiclav 625 3 27.5 mg/kg 4 750 3 187.5a 3 375a 3 375 3 Pivmecillinam 400 2
Overgrowth of resistant strains Days of Number aerobic Gram- anaerobic administration of patients enterobacteria positive cocci bacteria enterobacteria C. difficile Candida spp. Reference
C. Edlund and C. E. Nord cephradine cause minor alterations. However, administration of cefixime also leads to significant suppression of the anaerobic microflora. Most orally administered cephalosporins are associated with an increase in the numbers of enterococci and significant colonization with C. difficile.
Cefixime In six volunteers given 400 mg cefixime daily for 2 weeks,19 the numbers of E. coli in the intestinal microflora decreased markedly and in four of the subjects the number of enterococci increased. Of the anaerobic bacteria, bifidobacteria disappeared in two subjects, clostridia in three and Bacteroides fragilis in one. C. difficile was isolated in four subjects. No development of resistance to cefixime was observed in the intestinal microflora. In all 10 subjects receiving 200 mg cefixime bd for 7 days,21 the number of enterococci in the intestinal microflora increased, and streptococci and E. coli were suppressed during cefixime treatment. The numbers of anaerobic cocci, clostridia and bacteroides also decreased significantly. C. difficile was recovered from five subjects.
Effect of oral quinolones on the microflora (Table III) Ciprofloxacin In a study of 12 volunteers who received ciprofloxacin 500 mg bd for 7 days,24 Enterobacteriaceae were eliminated from the intestinal microflora and the number of streptococci decreased significantly. The anaerobic microflora was not affected. In 15 patients treated with ciprofloxacin 500 mg bd for a mean period of 42 days, the number of Enterobacteriaceae, anaerobic Gram-positive cocci and anaerobic Gram-positive rods in the intestinal microflora was markedly reduced.25 In 12 subjects receiving ciprofloxacin 400 mg bd for 7 days, E. coli was eliminated but the anaerobic intestinal microflora was not affected.26 The effect of ciprofloxacin 500 mg bd for 5 days was examined in 12 subjects by Bergan et al.27 The number of Enterobacteriaceae and enterococci decreased; the anaerobic microflora was not significantly affected. The microflora returned to normal within 2 weeks. In 12 people who received low-dose ciprofloxacin (50 mg qds) for 6 days,28 Enterobacteriaceae disappeared from the intestinal microflora and the number of enterococci changed slightly. The microflora returned to normal after 1 week. In six subjects given ciprofloxacin 500 mg od for 7 days,29 the number of Enterobacteriaceae in the intestinal microflora was suppressed; two of these subjects were colonized by ciprofloxacin-resistant staphylococci and corynebacteria. No marked alterations in the anaerobic bacteria were observed. Esposito et al.30 studied the effect of ciprofloxacin 250 mg bd or 500 mg od on the intestinal microflora of 14 patients with liver cirrhosis. Enterobacteriaceae were significantly suppressed but no major changes were observed in Gram-positive cocci or anaerobic bacteria. The microflora returned to normal within 2 weeks after treatment. In a study of the effect of ciprofloxacin in young adults and elderly persons,31 seven young and seven elderly individuals were given ciprofloxacin 500 mg bd for 5 days. Enterococci, streptococci, staphylococci and Enterobacteriaceae were suppressed and there were minor changes in the anaerobic microflora in both age groups. The intestinal microflora of 17 persons travelling to Mexico was investigated.32 All 17 subjects with diarrhoea were treated with ciprofloxacin 250 mg bid for 3 days. Enterobacteriaceae were suppressed significantly and anaerobic cocci and bifidobacteria increased in numbers during the ciprofloxacin treatment.
Cefpodoxime proxetil The effect of cefpodoxime proxetil on the intestinal microflora was examined by Brismar et al.12 Cefpodoxime proxetil at a dosage of 200 mg bd for 7 days was given to 10 subjects. Streptococci, enterobacteria and clostridia were significantly depressed whereas enterococci increased markedly. Three subjects were colonized by C. difficile and yeasts.
Cefprozil In eight volunteers who received 500 mg cefprozil bd for 8 days,22 there were minor increases in the number of enterococci, staphylococci and bacteroides in the intestinal microflora and a moderate decrease in Enterobacteriaceae during the administration of cefprozil. Three volunteers harboured C. difficile strains.
Ceftibuten Brismar et al.23 studied the effect of ceftibuten on the intestinal microflora in 14 volunteers receiving ceftibuten 400 mg/day for 10 days. Reductions in E. coli and anaerobic cocci and an increase in enterococci were observed during the same period. C. difficile was isolated from six volunteers.
Cephradine In six subjects given cephradine 1 g bd for 7 days,17 the number of staphylococci in the intestinal microflora decreased significantly but no other marked alterations were seen.
Comments Orally administered cephalosporins such as cefpodoxime, cefprozil and ceftibuten often result in moderate decreases in the number of Enterobacteriaceae, whereas cefaclor and 44
Table III. Effect of oral quinolones on the intestinal microflora Effect on Agent Ciprofloxacin
Lomefloxacin Levofloxacin Norfloxacin
500 2 500 2 400 2 500 2 50 4 500 1 250 2 500 1 500 2 250 2 400 2 400 1 400 1 400 1 500 1 100 2 200 2 400 2 100 2 200 2 400 2 400 2 200 2 400 2 200 2
Overgrowth of resistant strains Days of Number aerobic Gram- anaerobic administration of patients enterobacteria positive cocci bacteria enterobacteria C. difficile Candida spp. Reference 7 mean 42 7 5 6 5 5–10 5–10 5 3 7 7 5 7 10 7 7 7 7 5 5 8 5 5 7
12 15 12 12 12 6 7 7 14 17 10 10 5 10 10 10 10 10 10 10 10 10 6 6 10
– – – – – – – – – – – – – – – –
– – – – – – – – – – – – – – – – – – – –
– – – – – – – – – – – – – – – – – – – – – – – –
– – – – – – – – – – – – – – – – – – – – – – – – –
– – – – – – – – –
– – – – – – – – – – – –
24 25 26 27 28 29 30 30 31 32 33 34 35 36 34 37 37 37 38 38 38 39 40 40 41
, strong suppression (4 log10 cfu/g faeces); , mild to moderate suppression (2–4 log10 cfu/g faeces); , increase in number of microorganisms during therapy; , marked increase; –, no significant change.
Oral antibiotics and normal microflora
45
Enoxacin Ofloxacin
Dose mg/day
C. Edlund and C. E. Nord microflora were unaffected. The microflora returned to normal within 14 days.
Enoxacin In 10 subjects who received enoxacin 400 mg bd for 7 days,33 the number of enterococci, streptococci and micrococci in the intestinal microflora was not altered, Enterobacteriaceae decreased markedly and anaerobic bacteria were not significantly affected. The microflora returned to normal within 2 weeks after the end of treatment.
Comments Quinolones eliminate or strongly suppress intestinal Enterobacteriaceae. Quinolones other than norfloxacin also affect enterococci and anaerobic microorganisms to a minor degree. In general, the quinolones do not induce overgrowth of resistant bacteria or yeasts.
Levofloxacin and ofloxacin In a study by Edlund et al.,34 10 volunteers were given levofloxacin 500 mg od and 10 volunteers ofloxacin 400 mg od for 7 days. Levofloxacin and ofloxacin had similar effects on the intestinal microflora: the numbers of enterococci, Enterobacteriaceae and clostridia were suppressed markedly in both treatment groups. The microflora returned to normal within 2 weeks after the end of treatment. In five subjects given 400 mg ofloxacin od for 5 days,35 the number of enterococci in the intestinal microflora was reduced and Enterobacteriaceae were eliminated. Anaerobic bacteria were not markedly affected. The microflora returned to normal after the administration of ofloxacin had stopped.
Conclusions Ecological disturbances in the normal intestinal flora caused by antimicrobial agents vary not only between groups of agents but also between the agents in one class, because of variation in pharmacokinetics, in vitro activities and inactivation of the drug in the gastrointestinal tract. Of the agents commonly used to treat UTIs, β-lactam antibiotics such as ampicillin and amoxycillin often lead to overgrowth of resistant Enterobacteriaceae, while pivmecillinam reduces the number of E. coli without selecting resistant strains. None of the penicillins is associated with overgrowth of C. difficile, in contrast to the cephalosporins where such overgrowth is commonly reported. Quinolones tend to selectively suppress Gram-negative bacteria without a concomitant overgrowth of resistant strains. However, clinical reports on the increasing prevalence of quinolone-resistant Enterobacteriaceae, Pseudomonas aeruginosa and staphylococci may be of concern.42 In conclusion, when antimicrobial agents are prescribed for the treatment of UTIs, not only the antimicrobial spectrum of the agent, but also the presumed ecological disturbance, including risk of emergence of resistant strains, should be taken into consideration.
Lomefloxacin In 10 subjects receiving lomefloxacin 400 mg od for 7 days,36 the number of Enterobacteriaceae in the intestinal microflora was significantly reduced, the number of enterococci did not change and anaerobic bacteria in the microflora were only affected slightly. The microflora had returned to normal 2 weeks after the administration of lomefloxacin had stopped.
Norfloxacin
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In 10 volunteers given norfloxacin 200 mg od or 400 mg bd for 7 days,37 the number of Enterobacteriaceae in the intestinal microflora was suppressed. Numbers of enterococci and anaerobic bacteria did not change. In 10 subjects receiving norfloxacin 100, 200 or 400 mg bd for 7 days,38 Enterobacteriaceae disappeared from the intestinal microflora with all three dosages while enterococci were partially affected. No changes in the anaerobic microflora occurred. In 10 individuals receiving norfloxacin 400 mg bd for 8 days,39 the number of Enterobacteriaceae in the intestinal microflora decreased and the anaerobic microflora was unchanged. Fourteen days after norfloxacin treatment, the microflora had returned to normal. In 12 people receiving norfloxacin 400 or 800 mg od for 5 days,40 the number of Enterobacteriaceae in the intestinal microflora was markedly reduced and no changes in the anaerobic microflora were observed. In another study,41 10 subjects were given norfloxacin 200 mg bd for 7 days. The number of Enterobacteriaceae decreased significantly; the anaerobic
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