Referenced papers were identified through Medline with the retrieval engine of the US National Library of Medicine, and through personal communication with authors. Only papers published in English from 1991 and studies in human beings were included. Search terms were: microorganism or bacteria in combination with the generic names of antimicrobial agents. Combinations of normal, faecal, intestinal, saliva, oropharyngeal, vaginal, urethral microflora, and the generic names of antibacterial
ReviewEffect of antimicrobial agents on the ecological balance of human microflora
Introduction
In health there is an ecological balance between the human host and microorganisms that colonise mucous surfaces and the skin. The individual indigenous microbiota, often referred to as the normal microflora, is relatively stable at each ecological habitat, whereas there are greater differences between individuals depending on variations in diet and habits. The normal microflora represents a complex and important ecological system and alterations in the flora may give rise to serious clinical implications. The normal microflora acts as a barrier against colonisation by potentially pathogenic microorganisms and against overgrowth of already present microorganisms like yeasts or Clostridium difficile in the intestinal tract. The control of growth of opportunistic microorganisms is termed colonisation resistance,1 and is maintained not only by the normal flora, but also by several anatomical and physiological factors such as peristalsis of the intestines and secretion of saliva, sweat, and gastric acid.2
Administration of antimicrobial agents causes disturbances in the ecological balance between host and microorganisms. To what extent disturbances occur depends on the spectrum of the agent, the dose, the route of administration, pharmacokinetic and pharmacodynamic properties, and in-vivo inactivation of the agent. Incomplete absorption of orally administered drugs (figure) can influence the intestinal microflora and secretion of an antimicrobial agent by intestinal or vaginal mucosa, bile, salivary glands, or eccrine or apocrine sweat glands may interfere with the normal flora at different habitats. As a consequence, antibiotic-resistant microorganisms may increase in numbers.
Knowledge about the ecological impact of antimicrobial agents is of great clinical importance. Several investigations of the subject have been done during the past decades and studies published from 1965 to 1993 have been reviewed previously.3 Since then new drugs have been introduced and some older drugs have been re-evaluated. The aim of the present article is to compile the new data to give complete coverage of present knowledge.
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Phenoxymethylpenicillin
Adamsson et al4 investigated the effect of phenoxymethylpenicillin on the oropharyngeal and intestinal microflora of healthy volunteers. The number of viridans streptococci and the total number of anaerobic oropharyngeal microorganisms were suppressed during the administration period. No significant alterations of the intestinal microflora were observed although three volunteers became newly colonised with Klebsiella species (Table 1, Table 2).
Sjöberg et al5 examined the influence of
Parenterally administered cephalosporins
The spectra of cephalosporins are wider than that of penicillins and greater disturbances in the normal microflora might be expected, in particular of agents that excreted biliary like ceftriaxone. There is an increased risk of developing diarrhoea, and of colonisation of Cl difficile and yeasts in connection with treatment.18
Perorally administered cephalosporins
Like penicillins, cephalosporins are water-soluble and only low concentrations are detected in saliva. The agents are poorly absorbed, with the exception of loracarbef, and they are eliminated mainly via the kidneys. An inverse relationship has been shown between production of betalactamases and the concentration of cephalosporins in faeces.10 A high beta-lactamase activity by the normal microflora reduces the drug levels and the ecological alterations. Treatment with orally administered
Carbapenems
Carbapenems have the broadest spectra of the beta-lactam antibacterial agents. Faecal elimination of these agents is very small, while changes in the intestinal microflora are only moderate, which has also been shown for imipenem in earlier studies.3
Clindamycin
Clindamycin is mainly excreted in bile leading to very high concentrations in faeces and major ecological disturbances. Cl difficile-induced diarrhoea/colitis is common. Enterobacteria and enterococci are intrinsically resistant. The effect of clindamycin on the intestinal flora of healthy people was investigated by Orrhage et al34 An increase in enterococci and enterobacteria other than E coli and a substantial decrease in total anaerobic numbers was seen. The numbers of lactobacilli,
Quinupristin/dalfopristin
The impact of intravenous infusions of quinupristin/ dalfopristin on the faecal flora of healthy volunteers was investigated by Scanvic-Hameg and colleagues.35 Administration of the drug gave decreased numbers of Gram-negative anaerobic microorganisms and increased numbers of enterococci and enterobacteria. There was also an increase in numbers of enterococci and Gram-negative anaerobic bacteria resistant to quinupristin/dalfopristin.
Macrolides
Macrolides are detected in saliva in low concentrations and alterations are seen mainly in the aerobic microflora. The absorption of macrolides is incomplete, in particular that of erythromycin, and high faecal concentrations strongly affect the normal intestinal microflora. Enterobacteria are resistant to macrolides but the high faecal concentrations influence the numbers and also leads to overgrowth of highly resistant strains. Erythromycin affects not only the aerobic microflora but has also
Tetracyclines
No recent studies on the impact of tetracyclines on the normal microflora have been published. Older studies showed that administration gives rise not to quantitative changes, but rather to qualitative changes–ie, major overgrowth of resistant aerobic and anaerobic microorganisms occurs.3
Glycopeptides
Because of poor absorption after oral administration, oral glycopeptides are not used for treatment of infections with the exception of Cl difficile induced diarrhoea/colitis. In all studies dealing with the impact on the normal intestinal microflora, oral dosages were used. The poor absorption leads to very high intraluminal concentrations and striking disturbances in the intestinal microflora. Administration resulted in a selection of highly resistant enterococci and an increase in numbers of
Linezolid
Lode and colleagues investigated the ecological effects of linezolid—a new synthetic antibiotic—on the intestinal flora.15 They observed a significant reduction of enterococci and a substantial increase of klebsiella strains on day 8. All enterobacteria were resistant to linezolid. The numbers of bifidobacteria, lactobacilli, clostridia, and bacteroides were markedly reduced. MIC values for Bacteroides fragilis strains increased during administration and returned to pretreatment values on day
Telithromycin
Healthy subjects were enrolled to study the ecological impact of telithromycin on the oropharyngeal and intestinal microflora.39 In saliva, only the number of corynebacteria was significantly reduced and a transient colonisation with low numbers of enterobacteria was recorded in five participants. In the oral anaerobic microflora, Actinomyces and Prevotella species were moderately suppressed (table 7). Telithromycin caused moderate disturbances in the faecal flora. Numbers of E coli were
Metronidazole
Oral administration of metronidazole to patients with respiratory-tract, intra-abdominal, or urinary-tract infections resulted in slight changes in the numbers of enterococci and enterobacteria in the faecal microflora.44 Only minor changes were observed in the anaerobic faecal microflora (table 6).
Patients with H pylori infections were treated with omeprazole (20 mg twice per day for 7 days) and metronidazole in combination with either amoxicillin (OAM) or clarithromycin (OCM).45 The effects
Co-trimoxazole (trimethoprim/sulphamethoxazole)
Young girls were treated with co-trimoxazole and the periurethral microflora was examined.13 No major changes were registered in total bacterial counts or numbers of different microorganisms. All girls were free from enterobacterial colonisation during the study period (table 3).
The effect of co-trimoxazole on the aerobic intestinal microflora of women with recurrent urinary tract infections was investigated.46 The number of Enterobacteriaceae was strongly suppressed and one individual was
Nitrofurantoin
Nitrofurantoin macrocrystals were used as prophylactics for women with recurrent urinary tract infections.46 The influence on the aerobic faecal microflora was evaluated. The treatment did not alter the numbers of enterobacteria, enterococci, or yeasts (table 6). Nitrofurantoin is well absorbed and eliminated very quickly via the kidneys, which accounts for the minor impact on the intestinal microflora.
Quinolones
The fluoroquinolones are rapidly absorbed after oral administration and are distributed to most tissues and body secretions. Elimination of fluoroquinolones varies between agents and several mechanisms can be involved. The pathways for elimination include renal mechanisms, liver metabolism, and transluminal excretion. Very high concentrations are achieved in faeces but the major part is probably bound to faecal material, which reduces the amount of active drug.47 Some newer quinolones exhibit
Conclusions
The vast majority of studies of the impact of antimicrobial agents on the normal microflora have been carried out on the intestinal microflora. Emergence of antimicrobial resistance frequently originates from this dense intestinal microbial population, which also is an important source of pathogens. Most studies have been done in healthy people, since in severely ill patients the normal microflora is unpredictable. A balanced microflora is of importance to reduce the opportunities for pathogens
Search strategy and selection criteria
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