Elsevier

Journal of Infection

Volume 79, Issue 6, December 2019, Pages 471-489
Journal of Infection

Review
The effect of antibiotics on the composition of the intestinal microbiota - a systematic review

https://doi.org/10.1016/j.jinf.2019.10.008Get rights and content

Highlights

  • Antibiotics cause profound changes in the intestinal microbiota. These changes including a decrease in bacterial diversity, changes in the abundances of certain bacteria and an increase in antibiotic resistance.

  • The longest duration of changes was observed after treatment with ciprofloxacin (one year), clindamycin (two years) and clarithromycin plus metronidazole (four years). However, these findings are limited by follow-up times.

  • Understanding the effects of antibiotics on the intestinal microbiota will help tailor antibiotic treatment to minimise this ‘collateral damage’.

Abstract

Objective

Antibiotics change the composition of the intestinal microbiota. The magnitude of the effect of antibiotics on the microbiota and whether the effects are short-term or persist long-term remain uncertain. In this review, we summarise studies that have investigated the effect of antibiotics on the composition of the human intestinal microbiota.

Methods

A systematic search was done to identify original studies that have investigated the effect of systemic antibiotics on the intestinal microbiota in humans.

Results

We identified 129 studies investigating 2076 participants and 301 controls. Many studies reported a decrease in bacterial diversity with antibiotic treatment. Penicillin only had minor effects on the intestinal microbiota. Amoxicillin, amoxcillin/clavulanate, cephalosporins, lipopolyglycopeptides, macrolides, ketolides, clindamycin, tigecycline, quinolones and fosfomycin all increased abundance of Enterobacteriaea other than E. coli (mainly Citrobacter spp., Enterobacter spp. and Klebsiella spp.). Amoxcillin, cephalosporins, macrolides, clindamycin, quinolones and sulphonamides decreased abundance of E. coli, while amoxcillin/clavulante, in contrast to other penicillins, increased abundance of E. coli. Amoxicllin, piperacillin and ticarcillin, cephalosporins (except fifth generation cephalosporins), carbapenems and lipoglycopeptides were associated with increased abundance of Enterococcus spp., while macrolides and doxycycline decreased its abundance. Piperacillin and ticarcillin, carbapenems, macrolides, clindamycin and quinolones strongly decreased the abundance of anaerobic bacteria. In the studies that investigated persistence, the longest duration of changes was reported after treatment with ciprofloxacin (one year), clindamycin (two years) and clarithromycin plus metronidazole (four years). Many antibiotics were associated with a decrease in butyrate or butryrate-producing bacteria.

Conclusion

Antibiotics have profound and sometimes persisting effects on the intestinal microbiota, characterised by diminished abundance of beneficial commensals and increased abundance of potentially detrimental microorganisms. Understanding these effects will help tailor antibiotic treatment and the use of probiotics to minimise this ‘collateral damage’.

Introduction

The human intestine is the habitat for a rich and diverse community of microbes consisting of archaea, bacteria, eukaryota (fungi, helminths, and protozoans) and viruses. So far, more than 1000 bacterial species have been identified,1 but it has been suggested that there might be up to 36,000 different species of bacteria living in the intestine.2 Even though it was previously thought that 80% of the intestinal microbiota cannot be cultured,3 the main genera (such as Bacteroides spp., Bifidobacterium spp., Clostridium spp., Enterobacteriaceae, Enterococcus spp., Lactobacillus spp. and Veillonella spp.) are regularly identified in bacterial cultures. More recently, novel methods using selective culture media have enabled the majority of species within the microbiota to be cultured.4,5 Metagenomic shotgun sequencing provides a more in-depth analysis of the intestinal microbiota, including identification of bacterial species, resistance genes, as well as the identification of eukaroytes and viruses. Apart from being involved in various metabolic functions, the intestinal microbes are also crucial for the development of the immune system and regulation of immune responses. The complex interplay between a ‘healthy’ and ‘dysbiotic’ intestinal microbiota, which influences many health outcomes, remains incompletely understood.6, 7, 8

Antibiotics are among the most commonly prescribed drugs. Despite their benefits, their use has been associated with both short- and long-term adverse health outcomes, including increased risk of necrotising enterocolitis,9,10 bronchial hypersensitivity and asthma,11 obesity12 and autoimmune diseases.13 Antibiotic administration leads to perturbations in the intestinal microbiota through which some of these adverse health outcomes are likely mediated. This ‘collateral damage’ to the micobiota includes changes in abundance of certain taxa, a decrease in ‘colonisation resistance’ (protection against colonisation with potentially pathogenic (e.g. Enterobacteriaceae) or opportunistic (e.g. Clostridium difficile, Candida spp.)) organisms, and the development of antibiotic resistance.14 The human intestine has the highest density of microbes of all known environments. Bacteria living in the human intestine have a 25-fold higher rate of gene transfer than bacteria in other settings,15 and antibiotic exposure further increases horizontal gene transfer.16, 17, 18, 19, 20

The effect of antibiotics on the intestinal microbiota likely depends on the spectrum of activity (narrow vs broad spectrum), formulation, route of administration, pharmacokinetics and pharmacodynamics (e.g. biliary secretion), as well as dose and duration of administration. The extent of the effect of antibiotics on the composition of microbiota and whether the effects are only short-term or persist long-term remain uncertain. Additionally, it is uncertain whether antibiotic-resistant strains persist in the absence of selective pressure through antibiotics.

In this review, we summarise studies that have investigated the effect of antibiotics on the composition of the human intestinal microbiota. Understanding these effects will help tailor antibiotic treatment to minimise this ‘collateral damage’.

Section snippets

Systematic review methods

In January 2019, MEDLINE (1946 to present) was searched using the Ovid interface with the following search terms: (anti-bacterial agents OR anti-infective agents OR anti-microbial agents OR antibiotics OR antitubercular agents OR penicillins OR amoxicillin OR carbapenems OR cephalosporins OR macrolides OR quinolones OR glycopeptides OR aminoglycosides OR tetracyclines OR tigecycline OR daptomycin OR streptogramin OR linezolid OR colistin OR trimethoprim OR sulphonamides OR nitrofurantoin OR

Systematic review results

Our search identified 24,718 studies. Of these, 100 fulfilled the inclusion criteria. Hand-searching references identified 29 further relevant studies. The 129 studies included in this review investigated 2076 participants and 301 controls. The results of these studies are summarised in Table 1 and supplementary Tables 1 and 2.22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64

Discussion

This review shows that antibiotics have profound effects on the intestinal microbiota. Amoxicillin/clavulante, ciprofloxacin, minocycline, clindamycin, paromomycin and clarithromycin plus metronidazol were associated with decreased bacterial diversity,26,38,73,82,109,110,144 while amoxcillin and rifaximin did not influence bacterial diversity.26,138,139 Penicillin only had minor effects on the abundance of different taxa in the intestinal microbiota and did not increase resistance.22, 23, 24

CRediT authorship contribution statement

Petra Zimmermann: Writing - original draft. Nigel Curtis: Writing - review & editing.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgment

PZ is supported by a Fellowship from the European Society of Paediatric Infectious Diseases (ESPID).

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