ReviewAntibiotic resistance of bacterial biofilms
Introduction
Biofilm-growing bacteria cause chronic infections [1] characterised by persistent inflammation and tissue damage [2]. Chronic infections, including foreign-body infections, are infections that (i) persist despite antibiotic therapy and the innate and adaptive immune and inflammatory responses of the host and (ii) in contrast to colonisation, are characterised by an immune response and persisting pathology (Table 1).
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Occurrence and architecture of bacterial biofilms
Foreign-body infections are characterised by biofilm growth of bacteria on the outer and/or inner surface of the foreign body (Table 2). Biofilm growth also occurs on natural surfaces such as teeth [3], heart valves (endocarditis) [4], in the lungs of cystic fibrosis (CF) patients causing chronic bronchopneumonia [2], in the middle ear in patients with persistent otitis media [5], in chronic rhinosinusitis [6], in chronic osteomyelitis and prosthetic joint infections [7], [8], [9], in
Stationary-phase physiology, low oxygen concentration and slow growth
Inspection of environmental as well as in vitro biofilms has revealed that the oxygen concentration may be high at the surface but low in the centre of the biofilm where anaerobic conditions may be present [28]. Likewise, growth, protein synthesis and metabolic activity is stratified in biofilms, i.e. a high level of activity at the surface and a low level and slow or no growth in the centre, and this is one of the explanations for the reduced susceptibility of biofilms to antibiotics [29], [30]
Mutators
The mutation frequency of biofilm-growing bacteria is significantly increased compared with planktonically growing isogenic bacteria [32] and there is increased horizontal gene transmission in biofilms [33]. These physiological conditions may explain why biofilm-growing bacteria easily become multidrug resistant by means of traditional resistance mechanisms against β-lactam antibiotics, aminoglycosides and fluoroquinolones, which are detected by routine susceptibility testing in the clinical
Chromosomal β-lactamase and biofilm matrix components
Overproduction of chromosomally encoded AmpC cephalosporinase is considered the main mechanism of resistance of CF P. aeruginosa isolates to β-lactam antibiotics [50]. The most common β-lactamase production phenotype in CF isolates is the partially derepressed phenotype with high basal levels of β-lactamase that can be further induced to higher levels in the presence of β-lactam antibiotics [46]. The role of this β-lactamase phenotype is especially important for resistance to β-lactam
Tolerance, adaptive resistance and efflux pumps
Colistin is only antimicrobial active against the non-dividing central part of P. aeruginosa biofilms in vitro (Fig. 5B), whereas the superficial, metabolically active part of the biofilm becomes tolerant due to upregulation of the PmrA-PmrB two-component regulatory system involved in adaptive resistance to cationic peptides leading to addition of aminoarabinose to lipid A of LPS [24], [71], [72]. Since the metabolically active surface layer of the biofilm is susceptible to ciprofloxacin (Fig. 6
High cell density and quorum sensing (QS)
Bacteria communicate by means of synthesising and reacting on signal molecules [75], [76], [77], [78]. The term QS indicates that this system allows bacteria to sense when a critical number (concentration) of bacteria are present in a limited space in the environment and respond by activating certain genes that then produce, for example, virulence factors such as enzymes or toxins. The QS molecules are small peptides in many Gram-positive bacteria, whereas the most well described QS molecules
Quorum-sensing inhibitors (QSIs)
Much of our knowledge about QS originates from experiments with QS knock-out mutants and from the use of naturally occurring and artificially synthesised QSI compounds [84], [85]. Screening for QSIs in nature has identified many QSI compounds [86]. These naturally occurring QSI compounds can be synthesised and their structure modified and used to inhibit QS in vivo in experimental animal infections [84]. Since it has been shown that bacteria used for experimental animal biofilm infections
Prophylaxis and treatment of Pseudomonas aeruginosa biofilms in cystic fibrosis lungs: perspectives for other biofilm infections?
The currently used methods for preventing chronic P. aeruginosa biofilms in CF lungs are (i) prevention of cross-infection from other already chronically infected CF patients by isolation techniques and hygienic measures [101], (ii) early aggressive eradication therapy of intermittent colonisation by means of oral ciprofloxacin and nebulised colistin for 3 weeks or, even better, for 3 months or by using nebulised tobramycin as monotherapy [102] and (iii) daily nebulised DNase (Pulmozyme®) [103]
References (112)
- et al.
Isolation and biochemical characterization of extracellular polymeric substances from Pseudomonas aeruginosa
Methods Enzymol
(2001) - et al.
Persister cells and tolerance to antimicrobials
FEMS Microbiol Lett
(2004) - et al.
Gene transfer occurs with enhanced efficiency in biofilms and induces enhanced stabilisation of the biofilm structure
Curr Opin Biotechnol
(2003) - et al.
Characterization of the GO system of Pseudomonas aeruginosa
FEMS Microbiol Lett
(2002) - et al.
Chromosomal mechanisms of aminoglycoside resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients
Clin Microbiol Infect
(2009) - et al.
Spread of colistin-resistant non-mucoid Pseudomonas aeruginosa among chronically infected Danish cystic fibrosis patients
J Cyst Fibros
(2008) - et al.
Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience
J Cyst Fibros
(2008) - et al.
Sociomicrobiology: the connections between quorum sensing and biofilms
Trends Microbiol
(2005) - et al.
Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial
Lancet
(2002) - et al.
Long-term azithromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection; an observational cohort study
J Cyst Fibros
(2005)
Biofilms in infectious disease and on medical devices
Int J Antimicrob Agents
The application of biofilm science to the study and control of chronic bacterial infections
J Clin Invest
Pseudomonas aeruginosa biofilms in the respiratory tract of cystic fibrosis patients
Pediatr Pulmonol
Human oral bacterial biofilms
The role of immune complexes in the pathogenesis of bacterial infections
Annu Rev Microbiol
Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media
JAMA
Bacterial biofilms on the sinus mucosa of human subjects with chronic rhinosinusitis
Laryngoscope
Adherent bacterial colonization in the pathogenesis of osteomyelitis
Science
Prostetic joint infections: update in diagnosis and treatment
Swiss Med Wkly
Infection associated with prostetic joints
N Engl J Med
Epidemiology, medical outcomes and costs of catheter-related bloodstream infection in intensive care units of four European countries: litterature- and registry-based estimates
J Hosp Infect
Distribution, and ecology of bacteria in chronic wounds
J Clin Microbiol
Why chronic wounds won’t heal: a novel hypothesis
Wound Repair Regen
Foreign body infections—biofilms and quorum sensing
Ugeskr Laeger
Extracellular DNA required for bacterial biofilm formation
Science
Distribution of bacterial growth activity in flow-chamber biofilms
Appl Environ Microbiol
Biofilm formation by Pseudomonas aeruginosa wild type, flagella and type IV pili mutants
Mol Microbiol
Statistical analysis of Pseudomonas aeruginosa biofilm development: impact of mutations in genes involved in twitching motility, cell-to-cell signaling, and stationary-phase sigma factor expression
Appl Environ Microbiol
Biofilms: an overview of bacterial adhesion, activity, and control at surfaces
ASM News
Cell death in Pseudomonas aeruginosa biofilm development
J Bacteriol
Brief ultrasonication improves detection of biofilm-formative bacteria around a metal implant
Clin Orthop Relat Res
Enhanced activity of combination of tobramycin and piperacillin for eradication of sessile biofilm cells of Pseudomonas aeruginosa
Antimicrob Agents Chemother
Clinically feasible biofilm susceptibility assay for isolates of Pseudomonas aeruginosa from patients with cystic fibrosis
J Clin Microbiol
Silver against Pseudomonas aeruginosa biofilms
APMIS
Testing the susceptibility of bacteria in biofilms to antibacterial agents
Antimicrob Agents Chemother
Testing antimicrobial susceptibilities of adherent bacteria by a method that incorporates guidelines of the National Committee for Clinical Laboratory Standards
J Clin Microbiol
Microbial biofilms
Annu Rev Microbiol
Stratified growth in Pseudomonas aeruginosa biofilms
Appl Environ Microbiol
In situ growth rates and biofilm development of Pseudomonas aeruginosa populations in chronic lung infection
J Bacteriol
Increased mutability of Pseudomonas aeruginosa in biofilms
J Antimicrob Chemother
Pseudomonas aeruginosa and the biofilm mode of growth
Microbes Infect
High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection
Science
Occurrence of hypermutable Pseudomonas aeruginosa in cystic fibrosis patients is associated with the oxidative stress caused by chronic lung inflammation
Antimicrob Agents Chemother
Antibiotic resistance in Pseudomonas aeruginosa strains with increased mutation frequency due to inactivation of the DNA oxidative repair system
Antimicrob Agents Chemother
Hypermutation is a key factor in development of multiple-antimicrobial resistance in Pseudomonas aeruginosa strains causing chronic lung infections
Antimicrob Agents Chemother
Quorum sensing in Pseudomonas aeruginosa controls expression of catalase and superoxide dismutase genes and mediates biofilm susceptibility to hydrogen peroxide
Mol Microbiol
Hydrogen peroxide linked to lysine oxidase activity facilitates biofilm differentiation and dispersal in several Gram-negative bacteria
J Bacteriol
Role of mutation in Pseudomonas aeruginosa biofilm development
PLoS One
Endogenous oxidative stress produces diversity and adaptability in biofilm communities
Proc Natl Acad Sci USA
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