Managing Invasive Aspergillosis in haematological patients in the era of resistance PCR and increasing triazole resistance: a modelling study of different strategies.

OBJECTIVES: Triazole resistance in Aspergillus spp. is emerging and complicates prophylaxis and treatment of Invasive Aspergillosis (IA) worldwide. New Polymerase Chain Reaction (PCR) tests on broncho-alveolar lavage (BAL) fluid allow for detection of triazole-resistance on a genetic level, which opened up new possibilities for targeted therapy. In the absence of clinical trials, a modelling study delivers estimates of the added value of resistance detection with PCR and which empiric therapy would be optimal when local resistance rates are known.

DESIGN: We performed a decision-analytic modelling study based on epidemiological data of IA, extended with estimated dynamics of resistance rates and treatment effectiveness. We compared six clinical strategies that differ in use of PCR diagnostics (used versus not used) and in empiric therapeutic choice in case of unknown triazole-susceptibility: Voriconazole (VOR), Liposomal Amphotericin B (LAmB) or both. Outcome measures were proportion of correct treatment, survival and serious adverse events.

RESULTS: Implementing Aspergillus PCR tests was projected to result in residual treatment-susceptibility mismatches of <5% for a triazole resistance rate up to 20% (using VOR). Empiric LAmB outperformed VOR at resistance rates higher than 5-20%, depending on PCR use and estimated survival benefits of VOR over LAmB (figure 1). Combination therapy of VOR and LAmB performed best at all resistance rates but the advantage over the other strategies should be weighed against the expected increased number of drug related serious adverse events (figure 2). The advantage of combination therapy over LAmB monotherapy became smaller at higher triazole-resistance rates.

CONCLUSIONS: Introduction of current Aspergillus PCR tests on BAL-fluid is an effective way to increase the proportion of patients that receive targeted therapy for IA. The results indicate that close monitoring of background resistance rates and of adverse drug events are important to attain the potential benefits of LAmB. The choice of strategy ultimately depends on the probability of triazole-resistance, the availability of PCR and individual patient characteristics.