Report of the UK Cystic Fibrosis Trust Antibiotic Working Group

These bacteria can be harmless commensals or interact with other bacteria influencing their growthor behaviour. For example, a viridans streptococcus and a coagulase-negative staphylococcus from CFsputum were found to up-regulate genes involved in pathogenicity in P.aeruginosa. 9Infections with non-tuberculous mycobacteria, in particular Mycobacterium abscessus and the M.avium intracellulare complex are a major therapeutic challenge in CF (section 7). Aspergillus sp. maycause an immuno-pathological reaction – allergic broncho-pulmonary aspergillosis (section 7). Therole of Aspergillus sp. and other filamentous fungi such as Scedosporium apiospermum in other types offungal disease still awaits clarification.2.3 VariabilityChronic infection with P.aeruginosa is characterised by the appearance of different forms of bacterialcolony (morphotypes) including mucoid (hyper alginate producers) and small colony variants (SCV)– also known as dwarf colonies. SCVs are slow growing, so may be missed in the routine laboratoryand often have more antibiotic resistance than other isolates. 10 SCVs appear to adhere well to surfacesand may be involved in the development of biofilms (see below). Phenotypic variation seen inorganisms of the same genotype is not just limited to colonial variation. The degree of antibioticsusceptibility can also vary between bacteria of the same genotype and even the same morphotype ofP.aeruginosa in a single patient’s sample. 11;12 One consequence of this is that antibiotic susceptibilitytesting in vitro is poorly reproducible (different results can be obtained, depending upon whichbacteria are tested). Different colony types of S.aureus are seen in single samples from chronicinfection in CF, not the wide variety of morphotypes found in P.aeruginosa but classical colonies mixedwith slower growing SCVs with varied antibiotic susceptibility. 13 B.cepacia complex can also grow asdifferent morphotypes and show a range of antibiotic susceptibility. 142.4 HypermutatorsBacteria have systems to reduce the number of mistakes made when DNA replicates (“proof reading”).Hypermutators are bacteria with mutation in their DNA repair or error avoidance genes leading to anincrease in the intrinsic rate of mutation. Mutations can be deleterious or advantageous and it isthought that the repeated use of antibiotics in CF maintains a selection pressure that encourageshypermutators. 15 An early study showed that 37% of CF patients chronically infected withP.aeruginosa harboured mutator strains, one of the highest prevalence in a natural system. 16 Mutatorsare also common in other chronic lung diseases (non CF bronchiectasis and severe COPD) but rarein acute infections. 17 Hypermutator strains of H.influenzae, and S.aureus have also been found morefrequently in CF than in other conditions. 18;19 The practical impact of a high rate of spontaneousmutation is that if the population of bacteria is large enough in the CF lung, a sub-population ofbacteria with a mutation giving resistance to an antibiotic is likely to be present even before treatmentstarts, and will be selected if the patient is treated with that antibiotic on its own. 20 Data from in vitro,animal and clinical studies showed the selection of resistant strains with mono-therapy even beforehypermutators were described in CF. On this basis, expert consensus groups have recommended thatcombination antibiotics should be used to treat P.aeruginosa. 21 [C]2.5 BiofilmsIn acute infections it is thought that bacteria are free-floating (“planktonic”); they may adhere tosurfaces but do not form a structured aggregate. In contrast, biofilms comprise groups of bacteriaembedded in an acellular matrix usually attached to a surface. In CF the surface is the damaged wallof the airway and the matrix consists of bacterial products (predominantly alginate) plus materialderived from the patient’s cells. In chronic infection in CF, P.aeruginosa and the B.cepacia complex arethought to grow in biofilms in chronic infection. Although H.influenzae is not thought to causeCystic Fibrosis Trust 2.3March 2009