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Antibiotic resistance in chronic respiratory diseases: from susceptibility testing to the resistome

Hélène Pailhoriès, Jean-Louis Herrmann, Lourdes Velo-Suarez, Claudie Lamoureux, Clémence Beauruelle, Pierre-Régis Burgel, Geneviève Héry-Arnaud
European Respiratory Review 2022 31: 210259; DOI: 10.1183/16000617.0259-2021
Hélène Pailhoriès
1Laboratoire de Bactériologie, Institut de Biologie en Santé - PBH, CHU Angers, Angers, France
2HIFIH Laboratory UPRES EA3859, SFR ICAT 4208, Angers University, Angers, France
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Jean-Louis Herrmann
3Université Paris-Saclay, UVSQ, INSERM, Infection and Inflammation, Montigny-le-Bretonneux, France
4AP-HP, Groupe Hospitalo-Universitaire Paris-Saclay, Hôpital Raymond Poincaré, Garches, France
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Lourdes Velo-Suarez
5Brest Center for Microbiota Analysis (CBAM), Brest University Hospital, Brest, France
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Claudie Lamoureux
6Dept of Bacteriology, Virology, Hospital Hygiene, and Parasitology-Mycology, Brest University Hospital, Brest, France
7Université de Brest, INSERM, EFS, UMR 1078, GGB, Brest, France
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Clémence Beauruelle
6Dept of Bacteriology, Virology, Hospital Hygiene, and Parasitology-Mycology, Brest University Hospital, Brest, France
7Université de Brest, INSERM, EFS, UMR 1078, GGB, Brest, France
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Pierre-Régis Burgel
8Respiratory Medicine and National Cystic Fibrosis Reference Center, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Institut Cochin, INSERM U1016, Paris, France
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Geneviève Héry-Arnaud
5Brest Center for Microbiota Analysis (CBAM), Brest University Hospital, Brest, France
6Dept of Bacteriology, Virology, Hospital Hygiene, and Parasitology-Mycology, Brest University Hospital, Brest, France
7Université de Brest, INSERM, EFS, UMR 1078, GGB, Brest, France
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  • For correspondence: hery@univ-brest.fr
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  • FIGURE 1
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    FIGURE 1

    The respiratory resistome and its partners. The respiratory resistome is defined as the total of the antibiotic-resistance genes (ARGs) present in pathogenic and non-pathogenic bacteria in the respiratory airways. These ARGs can undergo mutations and spreading by horizontal gene transfer. A “core” resistome has been defined based on the similarity of ARGs found in healthy subjects and people with chronic respiratory disease (CRD). The “accessory” resistome refers to the resistome specific to CRD patients, and is affected by different factors, e.g. CRD pathophysiology, bacterial infection and antibiotic treatment. The resistome has an impact on the phenotypic antibiotic bacterial resistance, which is also affected by lung environment factors such as airway mucus composition, biofilm formation, bacterial interactions, human genetics and the immune response.

  • FIGURE 2
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    FIGURE 2

    Advantages, challenges and issues of resistome analysis in chronic respiratory diseases. Resistome data interpretation for the implementation of antibiotic resistance prediction relies on different strategies. A scoring system, based on analysis of mutations and horizontally acquired antibiotic-resistance genes (ARGs), has been developed [81]. Another method uses machine-learning strategies to predict phenotypic resistance by combining sequencing and transcriptome analysis [82]. Three-dimensional modelling, by building structural models, can also help in protein function prediction [64]. Functional metagenomics, which correlates phenotypic resistance and metagenomics data, can also provide insight into the interpretation of bacterial resistance [60]. However, some issues need to be settled. The variation in respiratory resistome data depending on the methodology used complicates inter-study comparison [83, 84]. Also, some variation in ARG abundance and resistome data can be associated with the intrinsic resistance of a single bacterial taxa, and needs to be correlated with microbiome analysis [53]. Finally, some difficulties can emerge in the phenotypic prediction of resistance to antibiotic molecules. SOP: standard operating procedure.

Tables

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  • TABLE 1

    Summary of antibiotic treatments recommended in CRDs

    Type of CRD
    IndicationCystic fibrosisCOPDSevere asthmaBronchiectasis
    Bacterial prophylaxisStaphylococcus aureus
     UK: flucloxacillin the first 3 years of life [15, 16]
     Other countries: not recommended   (uncertainty on clinical consequences   and on P. aeruginosa colonisation [17])
    NANANA
    Bacterial eradicationPseudomonas aeruginosa
     First-line treatment: 28 days of TIS or up   to 3 months of a combination of   nebulised colistin and oral   ciprofloxacin [16]
     Aggressive therapy: i.v. meropenem or   i.v. tobramycin [15]
    MRSA
     Combined oral and i.v. antibiotic   regimen (fusidic acid, rifampicin,   teicoplanin and vancomycin) [15]
    NANAP. aeruginosa
     First-line treatment: 14 days of oral ciprofloxacin
     If persistence of positive culture of sputum samples: i.v. treatment (e.g. β-lactam+aminoglycoside) or inhaled antibiotics (e.g. colistin, tobramycin or gentamicin) with a total duration of 3 months [18, 19]
    Chronic suppressive therapyP. aeruginosa
     Intermittent therapy: treatment with TIS   for 28 days (300 mg twice daily) on   alternate months (28-day on/off)
     Alternatives: TIP, inhaled aztreonam   lysine, colistimethate dry powder or   LIS [16, 20–22]
     Continuous daily administration mode   also increasingly recommended [23]
    Maintenance therapy
     Proposition of 6 months of oral   azithromycin with a 3 times a week   dose of 500 mg [27]
    Key pathogens
     Antibiotic courses administered 3 times per week [24]
    Maintenance therapies
     Infra-dose of azithromycin [25]
    Maintenance therapy
     Oral infra-dose of azithromycin for 48 weeks
     Azithromycin 3 times per week orally, in addition to inhaled corticosteroids and long-acting bronchodilators [7]
    Recurrent (≥3 per year) or severe acute PEx [19, 26]
     Long-term inhaled antibiotics (nebulised gentamicin, TIS, colistimethate dry powder, dry powder or liposomal ciprofloxacin), usually prescribed on alternate months [18]
     Long-term oral treatment with macrolide or other molecules [18, 26]
    Treatment of PExP. aeruginosa-induced PEx
     4 days with i.v. administration route [16];   oral or inhaled administration route   can also be used [15, 23]
    Other bacterial species-related PEx
     ≥2 antibiotics with different mechanisms   of actions [16]
    Antibiotic therapy: not systemically recommended [25, 28]
    Duration of antibiotic treatment: 5–10 days [28]
    Antibiotic therapy: not systemically recommended except in cases of documented pneumopathy [29]Antibiotic therapy: 14 days of antibiotics are recommended
    First-line: oral antibiotics
    In case of severity: i.v. ± inhaled colistimethate dry powder [18, 19, 26]

    CRD: chronic respiratory disease; COPD: chronic obstructive pulmonary disease; PEx: pulmonary exacerbations; NA: not applicable; TIS: tobramycin solution for inhalation; i.v.: intravenous; MRSA: methicillin-resistant Staphylococcus aureus; TIP: tobramycin inhaled powder; LIS: levofloxacin inhaled solution.

    • TABLE 2

      Impact of antibiotics on the respiratory microbiome in CRDs

      AntibioticSample analysedType of treatmentImpact of antibiotics on diversity of the microbiomeImpact on relative abundance of bacterial taxaDiseaseReference
      Association of different antibiotic class in treatment of CF exacerbation episodesSputumDiverse antibiotic treatments for a course of 8–9 years↓ α-diversity (inverse Simpson index)–CF[30]
      SputumDiverse antibiotics used for the treatment of acute PEx↑ Species richness through PEx and treatment periods, but return to the baseline state during recovery period↓ Prevotella melaninogenica and Streptococcus sanguinis
      ↑ Veillonella parvula during treatment period, but return to baseline state in post-recovery samples
      CF[31]
      SputumDiverse antibiotics used for the treatment of acute PExEither very little change through exacerbation cycle or return to baseline state on the post-recovery sampleNo taxa modification associated with clinical stage, including treatmentCF[32]
      Oral macrolidesOropharyngeal swab12 months of twice daily oral doses of 400 mg of erythromycinNo impact on α-diversity measuresDifference between treated and placebo groups:
      ↓ Actinomyces and Streptococcus
      ↑ Haemophilus after 48 weeks of treatment
      BE[33]
      Oropharyngeal swab6 months of 250 mg daily azithromycin for 5 days and then 250 mg 3 times per weekImpact on β-diversity measures↓ Fusobacteria
      ↑ Firmicutes during treatment compared with untreated group, but return to pre-treatment state after a 1-month washout period
      Severe asthma[34]
      Sputum12 months of low-dose azithromycin↓ Faith's phylogenetic diversity↓ Gammaproteobacteria (including H. influenzae) after 48 weeks of azithromycin treatment compared with placebo groupSevere asthma[35]
      Bronchoalveolar  lavage of the right upper lung lobe6 weeks of low-dose azithromycin↓ Shannon's diversity index↓ Prevotella, Staphylococcus and Haemophilus
      ↑ Anaerococcus between pre- and post-treatment state
      Moderate and severe asthma[36]
      SputumLow-dose erythromycinIncrease of genus richness between baseline and 48 weeks in treated group but no difference with placebo groupNo change in composition of airway microbiome in P. aeruginosa-dominated subgroup
      ↓ H. influenzae and ↑ P. aeruginosa in non-P. aeruginosa-dominated subgroup
      BE[37]
      SputumTreatment of exacerbations exclusively by antibiotics (without addition of corticosteroids) (two treatments azithromycin, one by ofloxacin, one by trimethoprim-sulfamethoxazole)–↓ of multiple taxa, mainly ProteobacteriaCOPD[38]
      β-lactamsNasal swabsVarious courses of treatments of several weeks, mostly (71%) β-lactams↑ Shannon's diversity index↓ Moraxellaceae
      ↑ other bacterial families (this increase was verified after more than one antibiotic treatment)
      CF[39]
      Bronchoalveolar lavage,  sputum or deep throat swabsCourses of treatment including β-lactams (25 of 31 involving a single β-lactam molecule) for acute PEx↓ α-diversity between exacerbation and treatment
      ↓ α-diversity at therapeutic doses between baseline and treatment
      ↑ α-diversity at sub-therapeutic doses at the same time points
      ↓ Haemophilus, Clostridiales and Lachnospiraceae
      ↑ Fusobacterium and Pseudomonas in the group treated at therapeutic doses between baseline and treatment samples
      No difference was observed in the sub-therapeutic group at the same time points
      No difference in the bacterial composition was observed in the two groups between post-recovery and baseline samples, or between exacerbation and treatment samples
      CF[40]
      SputumTreatment of exacerbation episodes, 19 of 23 treatments including β-lactamsMinimal impact on global community structure↓ RA of some low abundance taxa with antibiotic treatment: Gemella, two Pasteurella OTUs, two Streptococcus OTUs, Oribacterium and NeisseriaCF[41]
      SputumTreatment of exacerbation episodes by associations including at least one i.v. β-lactam↑ Shannon's diversity index in the first 72 h of treatment
      Return to the baseline state after 8–10 days of treatment
      ↓ P. aeruginosa
      ↑ anaerobes (Prevotella and Veillonella), in the first 72 h of treatment but return to the baseline state after 8–10 days of treatment
      CF[42]
      SputumCycle of 28 days of AZLI treatment followed by a 28-day period without treatmentNo significant change in Shannon's diversity index or Bray-Curtis β-diversity index in one AZLI cycle
      ↓ Shannon's diversity index
      ↓ Bray–Curtis β-diversity with ↑ AZLI cycles
      –CF[43]
      AminoglycosidesSputumA 1-month treatment with TIP↓ average species richness (Shannon and Simpson diversity indices) after 1 week of therapy
      Return to baseline state after the end of TIP therapy
      Most changes noticed between baseline state and first week of treatment occurring among low abundance taxa, mostly facultative and obligate anaerobes (Neisseria, Megasphaera, Granulicatella, Haemophilus, Streptococcus, Gemella, Rothia, Veillonella, Oribacterium)CF[44]
      SputumTIP or TIS during at least 1 yearNo difference in Shannon's diversity index↓ ParvimonasCF[45]

      CRD: chronic respiratory disease; CF: cystic fibrosis; PEx: pulmonary exacerbation; BE: bronchiectasis; COPD: chronic obstructive pulmonary disease; RA: relative abundance; OTU: operational taxonomic unit; i.v.: intravenous; AZLI: aztreonam lysine for inhalation; TIP: tobramycin inhaled powder; TIS: tobramycin inhaled solution.

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      Antibiotic resistance in chronic respiratory diseases: from susceptibility testing to the resistome
      Hélène Pailhoriès, Jean-Louis Herrmann, Lourdes Velo-Suarez, Claudie Lamoureux, Clémence Beauruelle, Pierre-Régis Burgel, Geneviève Héry-Arnaud
      European Respiratory Review Jun 2022, 31 (164) 210259; DOI: 10.1183/16000617.0259-2021

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      Antibiotic resistance in chronic respiratory diseases: from susceptibility testing to the resistome
      Hélène Pailhoriès, Jean-Louis Herrmann, Lourdes Velo-Suarez, Claudie Lamoureux, Clémence Beauruelle, Pierre-Régis Burgel, Geneviève Héry-Arnaud
      European Respiratory Review Jun 2022, 31 (164) 210259; DOI: 10.1183/16000617.0259-2021
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        • Impact of antibiotic therapy on the respiratory microbiome composition
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