Biofilms: what they are, why they cause persistent infection, and how research is changing treatment

1. What exactly is a biofilm?

A biofilm is a structured community of microbes—bacteria, fungi, or a mixture—that attaches to a surface and produces a self-generated protective matrix.

The building blocks

Biofilms contain:

• Cells: e.g., Aspergillus fumigatus, Pseudomonas aeruginosa, Staphylococcus aureus

• Extracellular polymeric substances (EPS):

  • Sticky sugars (polysaccharides)

  • Proteins

  • DNA released from dead cells (eDNA)

  • Lipids
    These form the thick “slime” layer.

Microbial ‘specialisation’

Within a biofilm, microbes change behaviour:

• Some become slow-growing persister cells, which survive drug exposure.

• Others produce signalling molecules (“quorum sensing”) to coordinate defence systems.

• The deeper layers become low-oxygen and acidic, making antifungals and antibiotics less effective.

Where do biofilms form in lung disease?

• In bronchiectatic airways, where mucus stagnates

• Around Aspergillus cavities in chronic pulmonary aspergillosis (CPA)

• In mucus plugs in ABPA

• In sinuses of patients with chronic fungal sinusitis

• On medical devices (catheters, stents)

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2. Why biofilms create so many problems

Biofilm problem 1: Immense drug resistance

Microbes in biofilms can be 100–1,000× more tolerant to antifungals/antibiotics.
This is due to:

• EPS matrix blocking drug penetration

• Slow metabolic rate → drugs that target growth become less effective

• Persister cells surviving even high doses

• Enzymes in the biofilm breaking down drugs

Aspergillus biofilms show increased resistance to:

• Azoles (itraconazole, voriconazole)

• Amphotericin B

• Echinocandins to a lesser extent

Pseudomonas biofilms resist:

• Ciprofloxacin

• Colistin (partially)

• Beta-lactams
  This helps explain your recent comment about Pseudomonas now being resistant even though you haven’t used ciprofloxacin for years—biofilms drive spontaneous resistance through evolution, stress responses, and gene exchange.

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Biofilm problem 2: Immune evasion

Immune cells (neutrophils, macrophages) cannot easily penetrate the EPS layer.
This leads to:

• Incomplete clearance → long-term infection

• Chronic inflammation → lung damage, fatigue

• Continuous mucus production triggered by inflammation

For Aspergillus, the fungus can switch genes on/off to avoid immune detection when it grows as a biofilm-like sheet rather than as airborne spores.

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Biofilm problem 3: Mixed infections behave differently

When bacteria and fungi coexist, they interact:

• Pseudomonas produces molecules that stimulate Aspergillus regrowth, or vice versa

• Each organism’s biofilm strengthens the other

• Mixed biofilms activate more intense inflammation

• They can shift the entire lung microbiome into a more disease-promoting “ecology”

This is why people with bronchiectasis or ABPA often experience:

• Frequent exacerbations

• Slow recovery

• Mucus plugging

• Worsening lung function over time

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3. Why people with aspergillosis and bronchiectasis are especially vulnerable

Stagnant mucus

Biofilms love:

• Thick mucus

• Low airflow

• Damp surfaces

All of which are present in:

• Bronchiectasis

• ABPA (due to mucus plugging)

• Chronic pulmonary aspergillosis

• Severe asthma with fungal sensitisation (SAFS)

Altered immunity

Long-term steroid use, high IgE, eosinophilia, and chronic inflammation all influence how readily biofilms form and how well the immune system can clear them.

Frequent antibiotic/antifungal exposure

This shapes the microbial community in a way that makes biofilms more likely and more resistant.

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4. What we are doing to tackle biofilms

1. Airway clearance is the single most effective biofilm disruptor

Physiotherapy techniques that help:

• ACTs (Active Cycle of Breathing Techniques)

• Oscillating devices (Flutter, Acapella)

• Postural drainage

• Autogenic drainage

• Saline nebulisation

These physically remove biofilms, which no drug can fully achieve alone.

2. Nebulised therapies

• Hypertonic saline (3–7%) helps break down mucus and destabilise the EPS matrix

• Inhaled antibiotics (tobramycin, colistin, aztreonam) target bacterial biofilms

• Nebulised antifungals are being explored, though not yet standard care

3. Anti-inflammatory control

Steroids/biologics help reduce airway swelling and mucus stasis, indirectly reducing biofilm formation.

4. Managing comorbidities

• Reducing reflux

• Improving sinus clearance

• Treating asthma aggressively

All reduce the “fuel” available to biofilms.

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B. Research and innovation

1. New antifungals with anti-biofilm activity

• Olorofim

• Fosmanogepix

• Ibrexafungerp

These show better penetration and less susceptibility to biofilm-related resistance.

2. Quorum sensing blockers

Compounds that prevent microbes from “communicating” so they cannot coordinate a biofilm. In trials for Pseudomonas.

3. Enzymes to dissolve the biofilm matrix

Research into:

• DNases

• Polysaccharide-breaking enzymes

• Surfactants

These aim to weaken the EPS “scaffolding”.

4. Microbiome-based approaches

Understanding how lung microbial ecosystems shift in disease could allow:

• Removal of harmful species

• Strengthening protective species

• Reducing biofilm formation overall

5. Combination therapies

Antifungal + antibiotic + mucolytic
is likely the future for patients with mixed fungal–bacterial biofilms.

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5. Key takeaways

• Biofilms are highly organised microbial fortresses that are difficult for drugs and the immune system to reach.

• They cause persistent infection, inflammation, and drug resistance.

• In aspergillosis and bronchiectasis, they play a central role in ongoing symptoms and flare-ups.

• Airway clearance remains the cornerstone of treatment today.

• New antifungals, antibiofilm agents, and microbiome therapies offer real hope for breaking biofilm-related disease cycles.

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