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]
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