Patient A and B had MIC’s of >16mgL for ITC this tells Essay

Patient A and B had MIC’s of >16mg/L for ITC, this tells us they are resistant to ITC as the eucast breakpoint is >2mg/L. Whereas patient C had an MIC of 1mg/L for ITC, which indicates a sensitivity to ITC therefore ITC should have worked. The mechanism which could explain this is it has been found that a deletion of the cdr1B gene can lead to an increased sensitivity to ITC, which could be a factor with patient C and explain why they are sensitive to ITC whereas patient A and B are not.

(Wang et al., 2013) For VRC patient’s A and B had MICs of 2mg/L and 4mg/L respectively which shows that while both were resistant patient B was slightly more resistant. Patent C had an MIC of >16mg/L which indicates a high resistance to VRC, this can be due to the mutations explored further in this discussion. All the patients showed a resistance to POS with an MIC of 0,5mg/L.

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The breakpoint being 0.25mg/L. All three patients were found to have a resistance to POS which suggests that there are additional non-cyp51A mechanisms occurring. A study conducted in Manchester found that out of 64 azole resistant strains taken from patients and the environment found that only 57% were found to have a mutation in the CYP51A gene therefore indicating that this is not the only source of resistance mechanism. (Bueid et al., 2010)These results were supported by the mutations found within the patient’s samples. Patient A and B both had an insertion of a 34bp tandem repeat which is normally always found with L98H substitution. It has been found that this mutation induces expression of CYP51A up to eight times the normal levels. (Liu et al., 2016) In over 90% of ITC resistant isolates these tandem repeats and L98H were found. It is unclear if these occurs due to common ancestral lineage migration or if it is due to repeated independent development in genetically unrelated strains. (Camps et al., 2012)It is hypothesised that an increase in mRNA levels in cellular CYP51A levels causes a reduction in the sensitivity of azoles. This mutation is the main resistance mechanism and is found in both patients receiving long term azole treatment and azole nave patients. It causes pan-azole resistance. Which could indicate that this mutation is causes using fungal pesticides in agriculture (Srinivasan, Lopez-Ribot and Ramasubramanian, 2014). Patient C had different mutations, which correlates with the MIC data produced. Patient C was found to be highly resistant to VRC, which has been shown can be caused by the Tr46/Y121F/T289A mutations, literature dictates that anything above >8mg/L is classed as being highly resistant. Patients C’s MIC to VRC was >16mg/L (Wiederhold, 2017).The role of Tr46 alongside the two mutations Y121F/T289A is unknown at this time. It has been found however that the genetic change due to T289A alongside the Tr46 has very little effect on the phenotype however when combined with Y121F has a big effect on the resistance gene. Y121F forms a H-bond with the heme centre in an enzyme. A disruption of the H-bond destabilises the active centre of the CYP51A gene. Within the CYP51A gene the threonine in position 289 is close to the azole moiety of VRC. The replacement of the polar T to an A which is more hydrophobic could promote a stable drug-protein interaction and therefore have an impact on ITC sensitivity (Snelders et al., 2015). It has also been found that a deletion of the cdr1B gene can lead to an increased sensitivity to ITC, which could be a factor with patient C and explain why they are sensitive to ITC whereas patient A and B are not (Wang et al., 2013).Efflux pumps such as ATP-binding cassettes (ABC) transporters and MFS (Major facilitator superfamily) transporters are important in eukaryote organism removing toxins from the cells. A.fumigatus contains 49 genes which encode for these. Thus, if there is an overexpression of these genes then this could lead to resistance to azoles as the concentration within the cell decreases as the cell would continuingly remove what they perceive to be toxic including the drug being used (Berger et al., 2017). Recent studies have found that mutations in the azole target gene found within environmental stains can lead to cross resistance between azole antifungals in patients and the environmental. Studies conducted on the genotype of epidemiologically and geographically unrelated strains deduced that each mutation could have originated from a common ancestor (Ren et al., 2017). The resistance these patients have developed could have come from either an environmental resistance or from long term azole treatment, which given that they all were suffering from cystic fibrosis, which leads them to become immunocompromised and therefore more susceptible to fungal infections is a real possibility and could have contributed to their death (Tashiro et al., 2011). The use of the prophylactic antifungal could also have contributed to their death as patient A was resistant to ITC and prophylactically treated with ITC, patient B was treated with POS and as the above data shows all three patients were resistant to POS and patient C was treated with VRC and was later show to be highly resistant to VRC. Once the fungal was identified patient A and C were treated with caspofungin and patient C with POS. However, Caspofungin is not an azole but a group of medication called an echinocandins, however as a treatment option, they have been found to be ineffective at completely inhibit the growth. This could explain why patient A and C both developed sepsis and failed to respond to treatment. (Walker, Gow and Munro, 2010) An explanation for why patient A and C were resistant to caspofungin and ITC are the production of the biofilms, these biofilms are characterised by aggregates of multicellular hyphae which are found in the extracellular matrix and are resistant to caspofungin and ITC. This could explain why patient A and C did not respond to the caspofungin (Kaur and Singh, 2013).

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