It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America

Understanding the molecular mechanisms underlying synergistic, potentiative and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations and multi-targeted agents. In this article, we describe an extensive investigation of the published literature on drug combinations for which the combination effect has been evaluated by rigorous analysis methods and for which relevant molecular interaction profiles of the drugs involved are available. Analysis of the 117 drug combinations identified reveals general and specific modes of action, and highlights the potential value of molecular interaction profiles in the discovery of novel multicomponent therapies.

Mechanisms of drug combinations: interaction and network perspectives.

Like other microorganisms, fungi exist in populations that are adaptable. Under the selection imposed by antifungal drugs, drug-sensitive fungal pathogens frequently evolve resistance. Although the molecular mechanisms of resistance are well-characterized, there are few measurements of the impact of these mechanisms on pathogen fitness in different environments. To predict resistance before a new drug is prescribed in the clinic, the full spectrum of potential resistance mutations and the interactions among combinations of divergent mechanisms can be determined in evolution experiments. In the search for new strategies to manage drug resistance, measuring the limits of adaptation might reveal methods for trapping fungal pathogens in evolutionary dead ends.

Evolution of antifungal-drug resistance: mechanisms and pathogen fitness

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(09)00204-1.pdf

Unveiling the role of network and systems biology in drug discovery.

Background : The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. Methods : Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. Results : Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30-1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12-0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16-0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. Conclusions : Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.

Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: A prospective, multicenter, observational study

Invasive fungal infections continue to cause significant morbidity and mortality among hospitalized patients. In particular, recent studies indicate an increase in the incidence of mould infections among transplant recipients, and Candida species have risen to be the third most common pathogen isolated among intensive care unit patients [1, 2]. Advances in modern medical treatment have led to growth in the at-risk population for fungal infections [3]. For example, Cryptococcus neoformans has re-emerged as a growing cause of invasive fungal disease due in large part to the development of novel immune therapy for malignancies, rheumatologic disorders, and management of rejection in transplant populations [4]. Unfortunately, these infections are associated with failures and high rates of relapse even when patients receive recommended therapy [5, 6]. Treatment of invasive mycoses continues to be challenging and complicated by the net state of immunosuppression among infected hosts combined with relative lack of efficacy, significant toxicity, drug–drug interactions, and drug resistance associated with available antifungal agents.

Conan MacDougall

Papers

Combination Antifungal Therapy