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The effect of antimicrobial agents on the ecology of the human intestinal microflora
VeterlnaryMtcrobtology, 35 ( 1 9 9 3 ) 193-197 Elsevier Science Publishers B.V., A m s t e r d a m
193
The effect of antimicrobial agents on the ecology of the human intestinal microflora C.E. Nord Department of Microbiology, Huddmge University Hospital, Karohnska Institute and National Bacterlologwal Laboratory, Stockholm, Sweden
ABSTRACT The most common and sigmficant cause of disturbances in the normal intestinal mlcroflora ~s the administration of ant~m~croblal agents. The mlcroflora can be influenced by anum~crobtal agents because of incomplete absorption of any orally administered antlmlcroblal agent, secretion of an anumlcrobml agent in the bile, or secretion from the intestinal mucosa. Admm~strauon of these agents may senously disturb the balance of the normal intestinal mtcroflora. This disturbance can cause bacterial overgrowth and emergence of resistant mlcroorgamsms which may lead to serious mfectxons and also encourage transfer of resistance factors among bactena. The ecological effects of penlcflhns. cephalosponns, monobactams, carbapenems, macrohdes, chndamycm, tetracychnes, nltro~m~dazoles and qumolones on the human mtestmal m~croflora are presented in this review article.
INTRODUCTION
The normal human intestinal microflora is remarkably stable over time. Continually strong forces are exerted by the different populations to maintain the stability of the flora. Though certain variations exist in the composition of the microflora and in the numbers of microorganisms between individuals, the population sizes of the various bacteria from the same individual appear to be very stable (Simon and Gorbach, 1981 ). The number of microorganisms in the human gastrointestinal tract depends mainly on the rate of passage of nutrients and on the acidity of the stomach contents. The main characteristics of the normal gastrointestinal flora are well defined. Only certain particular organisms belong to the normal flora, and there is a geographic localization of the specific organisms making the intestinal flora relatively constant over time (Bergogne-Berezin, 1989 ). Therapy with antimicrobial agents may cause pronounced disturbances in the normal intestinal microflora (Nord et al., 1986). Antimicrobial agents are important in the treatment and prophylaxis of infections. However, it Correspondence to: C.E. Nord, D e p a r t m e n t of Mlcrobmlogy, F 88, H u d d m g e U m v e r s t t y Hospital, S- 14186 Huddinge, Sweden.
0 3 7 8 - 1 1 3 5 / 9 3 / $ 0 6 . 0 0 © 1993 Elsevier Science P u b h s h e r s B.V. All fights reserved.
194
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should be considered that some of these agents have a harmful effect on the human microflora, leading to undesired effects such as overgrowth and superinfections with commensal microorganisms. A great deal of surgical infections appearing during antimicrobial treatment are caused by Gram-negative aerobic and anaerobic rods belonging to the normal intestinal microflora. There has been a change in responsible microorganisms in surgical infections from invading exogenous pathogens to potentially pathogenic indigenous microorganisms (Nord, 1990 ). A recent report concerning the relative occurrence of pathogens in intraabdominal infections revealed that Escherichia coli, Bacteroidesfragilis and Clostridium spp. accounted for the major part of the causative bacterial species (Wittman, 1991 ).
In vitro activittes and pharmacokinetic properties The potential of an antimicrobial agent to change the microbial colonization is related to its dose and pharmacokinetic properties. Oral drugs, that are poorly absorbed from the gastrointestinal tract or absorbed but also excreted in active form in the bile, have a significant impact on microbial colonization. Parenterally administered antimicrobial agents excreted in high concentrations in the intestinal tract can also cause significant changes in the microflora (Nord et al., 1986). Several antimicrobial agents cause changes in the intestinal microflora, the severity of which depends upon the agent's spectrum and concentration in the luminal contents. Oral administered antimicrobial agents that are well absorbed in the upper part of the small intestine have minor impact on the microflora in the large intestine. Antimicrobial agents that are poorly or incompletely absorbed can cause significant changes. Parenteral antimicrobial agents secreted into the bile or from the intestinal mucosa can also cause significant disturbances in the large intestinal microflora (Nord et al., 1986). Patients that are severely compromised by disease may be infected by exogenous microorganisms that colonize the gastrointestinal tract and at special risk are patients with low neutrophil counts. Many surgical infections that appear during antimicrobial treatment are caused by Gram-negative aerobic and anaerobic rods that normally inhabit the intestine. The responsible microorganisms in surgical infections have changed from invading exogenous pathogens to potentially pathogenic indigenous microorganisms.
Effect of antimicrobial agents on intestinal microflora Penicilhns Administration of ampicillin results in strong suppression of both the aerobic and anaerobic intestinal microflora while phenoxymethylpenicillin and
EFFECT OF ~NTIMICROBIAL AGENTS ON INTESTINa,L MICROFLORA
195
acid-resistant derivates of ampicillin like amoxicillin, bacampicillin, pivampicillin and talampicillin cause minor ecological alterations. Broad-spectrum penicillins, like pivmecillinam, azlocillin, temocillin and ticarcillin, cause significant changes in the intestinal microflora with strong suppression of aerobic Gram-negative bacteria and often overgrowth of Gram-positive aerobic bacteria. The anaerobic microflora is also suppressed by these agents (Nord and Edlund, 1991 ).
Cephalosporins Many cephalosporins such as cefuroxime, cephradine, cefazolin, cefaclor, cephrocile, cefotiam, cefotaxime, cefmenoxime, and loracarbef induce minor changes in the intestinal microflora, mainly on the Gram-negative aerobic bacteria. On the other hand some cephalosporins - cefixime, cefoperazone and ceftriaxone - cause strong suppression on the Gram-negative and Grampositive aerobic/anaerobic microflora. Most cephalosporins induce overgrowth or new colonization of resistant microorganisms during administration (Nord and Edlund, 1991; Nord et al., 1991 ).
Monobactams and carbapenems Aztreonam has a narrow antimicrobial spectrum only active against aerobic Gram-negative rods and in the intestinal microflora aztreonam suppresses enterobacteria markedly while an increase in the numbers of enterococci and staphylococci have been reported (Nord and Edlund, 1991 ). The carbapenems - imipenem and meropenem - have broad antimicrobial spectra covering both the aerobic and anaerobic bacteria in the intestinal microflora. Faecal eliminations are less than one per cent and only minor changes have been observed in the intestinal microflora (Nord and Edlund, 1991; Bergan et al., 1991 ).
Macrohdes Erythromycin, which has a broad antibacterial spectrum, induces changes both in the aerobic and anaerobic intestinal microflora due to high faecal concentrations. New colonization with erythromycin resistant microorganisms takes often place (Nord and Edlund, 1991 ). Dirithromycin is a new macrolide with in vitro activity similar to that of other macrolides. Dirithromycin causes significantly changes in the aerobic microflora thus the numbers of enterobacteria decrease while the numbers of streptococci and staphylococci increase. The anaerobic flora is also affected, i.e. Gram-positive cocci, bifidobacteria, eubacteria and bacteroides decrease while clostridia and lactobacilli increase. High faecal concentrations of dirithromycin is obtained which explains the ecological impact on the intestinal microflora ( Eckern~is et al., 1991 ).
196
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Clindamycin Clindamycin gives high concentrations in the intestine when administered either perorally or parenterally. This leads to pronounced changes in the aerobic and anaerobic intestinal microflora. Significant decreases in the number of anaerobic cocci and rods occur and clindamycin resistant clostridia, enterococci and enterobacteria proliferate (Nord and Edlund, 1991 ).
Tetracyclines Administration of tetracyclines causes minor decreases in the number of aerobic and anaerobic bacteria due to the rapid emergence of resistant strains in the normal intestinal microflora. Clinical manifestations such as diarrhoea and superinfection may then occur (Nord and Edlund, 1991 ).
Nitroimidazoles Nitroimidazoles are selectively active against anaerobic bacteria. Peroral administration of nitroimidazoles such as metronidazole or tinidazole induces no significant disturbances in the intestinal microflora. No microbiologically active concentrations of nitroimidazoles can be found in faeces. When nitroimidazoles are given intravenously to surgical patients, marked changes in the intestinal microflora have been observed. Enterococci and streptococci increase, whereas anaerobic cocci, Gram-positive rods, fusobacteria, and bacteroides decrease significantly. Concentrations of nitroimidazoles higher than the minimum inhibitory concentrations of anaerobic bacteria are noticed in the intestinal tract. Thus, the nitroimidazoles can have different ecological impacts depending on the route of administration (Nord and Edlund, 1991 ).
Quinolones The third generation of quinolones - ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, ofloxacin and pefloxacin - has an antibacterial activity mainly against facultative aerobic Gram-negative bacteria in the intestinal microflora. Administration of these quinolones cause marked suppression or elimination of enterobacteria while moderate effects on the enterococci are observed. In spite of the very high concentrations of these quinolones in faeces, the impact on the anaerobic microflora is minor. It has recently been shown that the quinolones have the ability to bind to faeces. The binding to faeces may explain the paradox of high concentrations in faeces versus the actual effect on the intestinal microflora (Nord and Edlund, 1991 ). CONCLUSIONS
Several factors influence the extent to which a given antimicrobial agent will effect the normal intestinal microflora. Predominant among these is the incomplete absorption of orally administered drugs. Poorly absorbed agents
EFFECT OF ANTIMICROBIALAGENTS ON INTESTINAL MICROFLORA
197
can reach the intestine in active form where they destroy susceptible microorganisms and change the ecologic balance. Parenterally administered agents that are secreted in the bile or from the intestinal mucosa also tend to destroy the normal microbial population. From the ecological point of view, there is therefore no foundation for the old rule that narrow spectrum antimicrobial agents should always be preferred over broad spectrum ones. Antimicrobial agents should be divided into ecological favourable and ecological non-favourable agents.
REFERENCES Bergan, T., Nord, C.E. and Thorstemsson, S.B., 1991. Effect of meropenem on the intestinal mlcroflora. Eur. J. Chn. Mlcroblol. Infect. Dis., 10: 524-527. Bergogne-Berezm, E., (Ed) 1989. Microbial ecology and intestinal refections, pp. 1-5. In: MIcrobml ecology and intestinal mfect~ons, Springer-Verlag, Pans. Eckern~s, S.A., Grahn6n, A. and Nord, C.E., 1991: Impact of dirithromycln on the normal oral and intestinal microflora. Eur. J. Chn. Mlcroblol. Infect. Dis., 10: 688-692. Nord, C.E., 1990: Studies on the ecological impact of antibiotics. Eur. J. Clin. Mlcroblol. Infect. Dis., 9: 517-518. Nord, C.E. and Edlund, C., 1991. Ecological effects of antlmicrobial agents on the human intestinal mlcroflora. M~crobml. Ecol. Health Dis., 4:193-207. Nord, C.E., Grahn6n, H. and Eckern~is, S.A., 1991. Effect ofloracarbefon the normal oropharyngeal and intestinal mlcroflora. Scand. J. Infect. Dis., 23: 255-260. Nord, C.E., Helmdahl, A. and Kager, L., 1986. AnUmlcroblal reduced alterations of the human oropharyngeal and intestinal m~croflora. Scand. J. Infect. Dis., 49: 64-72. Simon, G.L. and Gorbach, S.L, 1981. Intestinal flora m health and disease. In: L.R. Johnson (ed.), Physiology of the gastrointestinal tract, Raven Press, New York, pp. 136 I - 1380. Wlttman, D.H., 1991. Intra-abdommal refections. Pathophys~ology and treatment, pp. 20-29 Marcel Dekker, New York.
193
The effect of antimicrobial agents on the ecology of the human intestinal microflora C.E. Nord Department of Microbiology, Huddmge University Hospital, Karohnska Institute and National Bacterlologwal Laboratory, Stockholm, Sweden
ABSTRACT The most common and sigmficant cause of disturbances in the normal intestinal mlcroflora ~s the administration of ant~m~croblal agents. The mlcroflora can be influenced by anum~crobtal agents because of incomplete absorption of any orally administered antlmlcroblal agent, secretion of an anumlcrobml agent in the bile, or secretion from the intestinal mucosa. Admm~strauon of these agents may senously disturb the balance of the normal intestinal mtcroflora. This disturbance can cause bacterial overgrowth and emergence of resistant mlcroorgamsms which may lead to serious mfectxons and also encourage transfer of resistance factors among bactena. The ecological effects of penlcflhns. cephalosponns, monobactams, carbapenems, macrohdes, chndamycm, tetracychnes, nltro~m~dazoles and qumolones on the human mtestmal m~croflora are presented in this review article.
INTRODUCTION
The normal human intestinal microflora is remarkably stable over time. Continually strong forces are exerted by the different populations to maintain the stability of the flora. Though certain variations exist in the composition of the microflora and in the numbers of microorganisms between individuals, the population sizes of the various bacteria from the same individual appear to be very stable (Simon and Gorbach, 1981 ). The number of microorganisms in the human gastrointestinal tract depends mainly on the rate of passage of nutrients and on the acidity of the stomach contents. The main characteristics of the normal gastrointestinal flora are well defined. Only certain particular organisms belong to the normal flora, and there is a geographic localization of the specific organisms making the intestinal flora relatively constant over time (Bergogne-Berezin, 1989 ). Therapy with antimicrobial agents may cause pronounced disturbances in the normal intestinal microflora (Nord et al., 1986). Antimicrobial agents are important in the treatment and prophylaxis of infections. However, it Correspondence to: C.E. Nord, D e p a r t m e n t of Mlcrobmlogy, F 88, H u d d m g e U m v e r s t t y Hospital, S- 14186 Huddinge, Sweden.
0 3 7 8 - 1 1 3 5 / 9 3 / $ 0 6 . 0 0 © 1993 Elsevier Science P u b h s h e r s B.V. All fights reserved.
194
c E NORD
should be considered that some of these agents have a harmful effect on the human microflora, leading to undesired effects such as overgrowth and superinfections with commensal microorganisms. A great deal of surgical infections appearing during antimicrobial treatment are caused by Gram-negative aerobic and anaerobic rods belonging to the normal intestinal microflora. There has been a change in responsible microorganisms in surgical infections from invading exogenous pathogens to potentially pathogenic indigenous microorganisms (Nord, 1990 ). A recent report concerning the relative occurrence of pathogens in intraabdominal infections revealed that Escherichia coli, Bacteroidesfragilis and Clostridium spp. accounted for the major part of the causative bacterial species (Wittman, 1991 ).
In vitro activittes and pharmacokinetic properties The potential of an antimicrobial agent to change the microbial colonization is related to its dose and pharmacokinetic properties. Oral drugs, that are poorly absorbed from the gastrointestinal tract or absorbed but also excreted in active form in the bile, have a significant impact on microbial colonization. Parenterally administered antimicrobial agents excreted in high concentrations in the intestinal tract can also cause significant changes in the microflora (Nord et al., 1986). Several antimicrobial agents cause changes in the intestinal microflora, the severity of which depends upon the agent's spectrum and concentration in the luminal contents. Oral administered antimicrobial agents that are well absorbed in the upper part of the small intestine have minor impact on the microflora in the large intestine. Antimicrobial agents that are poorly or incompletely absorbed can cause significant changes. Parenteral antimicrobial agents secreted into the bile or from the intestinal mucosa can also cause significant disturbances in the large intestinal microflora (Nord et al., 1986). Patients that are severely compromised by disease may be infected by exogenous microorganisms that colonize the gastrointestinal tract and at special risk are patients with low neutrophil counts. Many surgical infections that appear during antimicrobial treatment are caused by Gram-negative aerobic and anaerobic rods that normally inhabit the intestine. The responsible microorganisms in surgical infections have changed from invading exogenous pathogens to potentially pathogenic indigenous microorganisms.
Effect of antimicrobial agents on intestinal microflora Penicilhns Administration of ampicillin results in strong suppression of both the aerobic and anaerobic intestinal microflora while phenoxymethylpenicillin and
EFFECT OF ~NTIMICROBIAL AGENTS ON INTESTINa,L MICROFLORA
195
acid-resistant derivates of ampicillin like amoxicillin, bacampicillin, pivampicillin and talampicillin cause minor ecological alterations. Broad-spectrum penicillins, like pivmecillinam, azlocillin, temocillin and ticarcillin, cause significant changes in the intestinal microflora with strong suppression of aerobic Gram-negative bacteria and often overgrowth of Gram-positive aerobic bacteria. The anaerobic microflora is also suppressed by these agents (Nord and Edlund, 1991 ).
Cephalosporins Many cephalosporins such as cefuroxime, cephradine, cefazolin, cefaclor, cephrocile, cefotiam, cefotaxime, cefmenoxime, and loracarbef induce minor changes in the intestinal microflora, mainly on the Gram-negative aerobic bacteria. On the other hand some cephalosporins - cefixime, cefoperazone and ceftriaxone - cause strong suppression on the Gram-negative and Grampositive aerobic/anaerobic microflora. Most cephalosporins induce overgrowth or new colonization of resistant microorganisms during administration (Nord and Edlund, 1991; Nord et al., 1991 ).
Monobactams and carbapenems Aztreonam has a narrow antimicrobial spectrum only active against aerobic Gram-negative rods and in the intestinal microflora aztreonam suppresses enterobacteria markedly while an increase in the numbers of enterococci and staphylococci have been reported (Nord and Edlund, 1991 ). The carbapenems - imipenem and meropenem - have broad antimicrobial spectra covering both the aerobic and anaerobic bacteria in the intestinal microflora. Faecal eliminations are less than one per cent and only minor changes have been observed in the intestinal microflora (Nord and Edlund, 1991; Bergan et al., 1991 ).
Macrohdes Erythromycin, which has a broad antibacterial spectrum, induces changes both in the aerobic and anaerobic intestinal microflora due to high faecal concentrations. New colonization with erythromycin resistant microorganisms takes often place (Nord and Edlund, 1991 ). Dirithromycin is a new macrolide with in vitro activity similar to that of other macrolides. Dirithromycin causes significantly changes in the aerobic microflora thus the numbers of enterobacteria decrease while the numbers of streptococci and staphylococci increase. The anaerobic flora is also affected, i.e. Gram-positive cocci, bifidobacteria, eubacteria and bacteroides decrease while clostridia and lactobacilli increase. High faecal concentrations of dirithromycin is obtained which explains the ecological impact on the intestinal microflora ( Eckern~is et al., 1991 ).
196
c E NORD
Clindamycin Clindamycin gives high concentrations in the intestine when administered either perorally or parenterally. This leads to pronounced changes in the aerobic and anaerobic intestinal microflora. Significant decreases in the number of anaerobic cocci and rods occur and clindamycin resistant clostridia, enterococci and enterobacteria proliferate (Nord and Edlund, 1991 ).
Tetracyclines Administration of tetracyclines causes minor decreases in the number of aerobic and anaerobic bacteria due to the rapid emergence of resistant strains in the normal intestinal microflora. Clinical manifestations such as diarrhoea and superinfection may then occur (Nord and Edlund, 1991 ).
Nitroimidazoles Nitroimidazoles are selectively active against anaerobic bacteria. Peroral administration of nitroimidazoles such as metronidazole or tinidazole induces no significant disturbances in the intestinal microflora. No microbiologically active concentrations of nitroimidazoles can be found in faeces. When nitroimidazoles are given intravenously to surgical patients, marked changes in the intestinal microflora have been observed. Enterococci and streptococci increase, whereas anaerobic cocci, Gram-positive rods, fusobacteria, and bacteroides decrease significantly. Concentrations of nitroimidazoles higher than the minimum inhibitory concentrations of anaerobic bacteria are noticed in the intestinal tract. Thus, the nitroimidazoles can have different ecological impacts depending on the route of administration (Nord and Edlund, 1991 ).
Quinolones The third generation of quinolones - ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, ofloxacin and pefloxacin - has an antibacterial activity mainly against facultative aerobic Gram-negative bacteria in the intestinal microflora. Administration of these quinolones cause marked suppression or elimination of enterobacteria while moderate effects on the enterococci are observed. In spite of the very high concentrations of these quinolones in faeces, the impact on the anaerobic microflora is minor. It has recently been shown that the quinolones have the ability to bind to faeces. The binding to faeces may explain the paradox of high concentrations in faeces versus the actual effect on the intestinal microflora (Nord and Edlund, 1991 ). CONCLUSIONS
Several factors influence the extent to which a given antimicrobial agent will effect the normal intestinal microflora. Predominant among these is the incomplete absorption of orally administered drugs. Poorly absorbed agents
EFFECT OF ANTIMICROBIALAGENTS ON INTESTINAL MICROFLORA
197
can reach the intestine in active form where they destroy susceptible microorganisms and change the ecologic balance. Parenterally administered agents that are secreted in the bile or from the intestinal mucosa also tend to destroy the normal microbial population. From the ecological point of view, there is therefore no foundation for the old rule that narrow spectrum antimicrobial agents should always be preferred over broad spectrum ones. Antimicrobial agents should be divided into ecological favourable and ecological non-favourable agents.
REFERENCES Bergan, T., Nord, C.E. and Thorstemsson, S.B., 1991. Effect of meropenem on the intestinal mlcroflora. Eur. J. Chn. Mlcroblol. Infect. Dis., 10: 524-527. Bergogne-Berezm, E., (Ed) 1989. Microbial ecology and intestinal refections, pp. 1-5. In: MIcrobml ecology and intestinal mfect~ons, Springer-Verlag, Pans. Eckern~s, S.A., Grahn6n, A. and Nord, C.E., 1991: Impact of dirithromycln on the normal oral and intestinal microflora. Eur. J. Chn. Mlcroblol. Infect. Dis., 10: 688-692. Nord, C.E., 1990: Studies on the ecological impact of antibiotics. Eur. J. Clin. Mlcroblol. Infect. Dis., 9: 517-518. Nord, C.E. and Edlund, C., 1991. Ecological effects of antlmicrobial agents on the human intestinal mlcroflora. M~crobml. Ecol. Health Dis., 4:193-207. Nord, C.E., Grahn6n, H. and Eckern~is, S.A., 1991. Effect ofloracarbefon the normal oropharyngeal and intestinal mlcroflora. Scand. J. Infect. Dis., 23: 255-260. Nord, C.E., Helmdahl, A. and Kager, L., 1986. AnUmlcroblal reduced alterations of the human oropharyngeal and intestinal m~croflora. Scand. J. Infect. Dis., 49: 64-72. Simon, G.L. and Gorbach, S.L, 1981. Intestinal flora m health and disease. In: L.R. Johnson (ed.), Physiology of the gastrointestinal tract, Raven Press, New York, pp. 136 I - 1380. Wlttman, D.H., 1991. Intra-abdommal refections. Pathophys~ology and treatment, pp. 20-29 Marcel Dekker, New York.