Medical research has linked fungus and cancer for many decades. With the origins of metabolic cancer research from Nobel Prize winner Otto Warburg to the Pleomorphic observations of Dr Günther Enderlein. More recently, Italian oncologist Dr Tullio Simonicini was ostracized for his work curing terminal cancer patients by treating them for localized and systemic fungal infections. And one of my personal hero’s in the field of oncology, Dr Thomas Seyfried, eloquently outlined the fermentative nature of the cancer cell and the dependance on sugar and amino acids (protein).
Recently, I came across this article posted on Medscape, a fairly conservative medical news site, about resistant candida infections in people with cancer. The article does not go into detail about the hypothesized cause of these fungal infections, only outlining a few potential associations. However, the scary thing is the degree of resistance and poor prognosis in patients with associated candida infections and the fact that I quantify fungal infections in people all the time!
With my vast reading on the underlying causes of cancer I could not state that cancer is unequivocally caused by fungal infection, however I certainly couldn’t say that it is not either. And if not of fungal origin, then what about the association of many types of cancer with viral infection.
Regardless of origin, one thing is clear! Inevitably, it is a weekend immune system and nutritionally depleted body that could allow such infections and cancer to develop in the first place.
But why are so many of us so week …. I chalk it up to emotional stress and lack of time to self nurture! Most of us are way to stressed out or burnt out and we love dietary convenience. This is why diet strategies like the GAPS diet are so essential to adapt into peoples lifestyles.
The basis is very simple, which includes trying to determine foods that make the individual sick or week, heeling the intestines with high amounts of collagen rich bone broth/stock and the regular consumption of fermented foods such as yogurt, kefir, sauerkraut, kombucha, kim chi, or natto.
I am now on full GAPS, after close to 2 months on the GAPS intro stages. I believe I have several sensitivities that I was not aware of, such as raw garlic and most grains so I have done my best to avoid these and am working on introducing more fermented foods and probiotics into my regime. I have also decided to do another food allergy test to see if anything shows up now that my body is more sensitive.
The GAPS diet has been very easy and extremely inexpensive. It is also really yummy, once you get past the first few stages! It is my belief that GAPS and other self nurturing strategies are the cure to most chronic disease and encourage everyone to give self nurturing a try!
Drug-Resistant Candida glabrata Infection in Cancer Patient
Dimitrios Farmakiotis, Jeffrey J. Tarrand, Dimitrios P. Kontoyiannis; Emerging Infectious Diseases. 2014;20(11):1833-1840. (http://wwwnc.cdc.gov/eid/article/20/11/14-0685_article)
Discussion
In this contemporary series of cancer patients with C. glabrata fungemia, the rates of in vitro caspofungin resistance and multidrug resistance are among the highest reported to date. By comparing the updated[10] with the previous, non–species-specific CLSI definitions of in vitro susceptibility,[16] we found that 90% of caspofungin-intermediate or -resistant C. glabrata bloodstream isolates would have been previously classified as susceptible. Caspofungin resistance was associated with previous exposure to echinocandins, use of TPN, and all-cause mortality rate.
Contrary to previous findings from our institution,[3] most patients with C. glabrata fungemia in the series reported here had solid tumors rather than hematologic malignancies. One third of fluconazole-resistant isolates and half of those with decreased susceptibility to caspofungin were isolated from patients with solid malignancies. These results probably reflect an overall increase in solid tumors; however, our findings also confirm that C. glabrata bloodstream infections have become major clinical problems among all patients at risk for candidemia.[6,9,14,15,17]
In agreement with previously reported findings, our study indicated that broad use of azoles—mainly voriconazole—and echinocandins was strongly associated with C. glabrata fluconazole and caspofungin resistance.[3,5,6,14,15] In our study, 11 C. glabrata isolates were classified as resistant without having had any previous documented exposure to the respective classes of antifungal drugs. This finding is in agreement with a recent report of isolation of 4 C. glabrata FKS mutants from patients who had not received echinocandins.[17] Because several factors place cancer patients at risk for candidemia and clinical failure of antifungal drugs,[1–5] we sought to identify those clinical factors associated with in vitro resistance. On the basis of our results, we consider it likely that poor host defense mechanisms associated with the presence of hematologic malignancy, myelosuppression, and critical illness are independently associated with resistance.
We also observed an independent association between TPN and caspofungin resistance or multidrug resistance. TPN is an established risk factor for candidemia and a marker of intestinal dysfunction.[18] Moreover, TPN causes atrophy of the intestinal mucosa, facilitating microperforations and Candida translocation, and it is associated with thick biofilm formation and catheter-related infections.[18,19] Whether our observed association between TPN and caspofungin resistance is reflective of critical illness or whether the above mechanisms also promote the development of resistance remains to be determined.
In our study, almost one third of fluconazole-resistant strains and two-thirds of caspofungin-resistant strains were multidrug resistant. These rates of cross-resistance are significantly higher than those previously reported from multi-institutional registries[20,21] and another tertiary academic hospital.[6] Specifically, investigators from Duke University Hospital reported a 25% rate of fluconazole resistance over a 10-year period, which is similar to our rate of 21%. In the same report,[6] the overall rate of resistance to at least 1 echinocandin was lower (6.7%) than that found in our study (10.7%), although by 2010 it had increased to 12.7%.[6] In another study, 11% of C. glabrata bloodstream isolates were resistant to caspofungin and 18% had FKS mutations.[17] Notably, the rates of multidrug resistance determined by the study from Duke (3.5%),[6] the Centers for Disease Control and Prevention SENTRY Antimicrobial Surveillance Program (1%),[20] and another recent multi-institutional study (1%)[21] were substantially lower than the rates of multidrug resistance determined in our study (6.8%). These data document a worrisome trend for concomitant resistance of C. glabrata clinical isolates to azoles and echinocandins, which seems to be more prominent in our population of patients with cancer.
In our study, resistance to fluconazole was highly associated with caspofungin resistance, independent of prior use of antifungal drugs; this finding is in agreement with our institution’s previously reported findings for different Candida species.[22] Echinocandin, but not azole, exposure was a significant independent predictor of multidrug resistance. These findings could reflect a worrisome potential for development of multidrug resistance in C. glabrata, a versatile, haploid species.[7] In a recent study, serial exposures of a C. glabrata laboratory strain to low-dose micafungin led to the development of a single-point mutation conferring multiazole and echinocandin resistance with preserved virulence.[23] Moreover, in an analysis of molecular events leading to echinocandin resistance of C. glabrata isogenic isolates consecutively obtained from a patient receiving chronic TPN, a multidrug-resistant strain emerged after multiple courses of treatment with caspofungin but no previous azole exposure.[8] Selective pressure from antifungal drugs, along with other factors, such as chemotherapy[24] and broad-spectrum antibacterial drugs,[25] might lead to the expansion of similar phenotypes.
By applying the updated clinical break points to our patient population, we captured a strong and potentially independent correlation of all-cause mortality rates with in vitro caspofungin MICs but not with other factors classically associated with poor outcomes such as advanced age and hematologic malignancy.[2,4,5] Although other residual confounders cannot be ruled out, this finding is in agreement with previously reported significant associations between clinical failure of echinocandins and elevated in vitro echinocandin MICs.[6,8,14,17] In some animal studies, FKS mutations leading to echinocandin resistance were associated with decreased fitness.[8,26] Nevertheless, a recent study that used an immunocompromised murine model of systemic candidiasis showed that caspofungin was ineffective against C. glabrata isolates with MIC ≥1 mg/L.[27] Furthermore, investigators have also described the development of compensatory mechanisms that override the decreased virulence resulting from clinical exposure of an FKS mutant C. glabrata isolate to an echinocandin.[8] Clinical[8,28] and laboratory[23] strains that exhibit high-level antifungal resistance without decreases in fitness have been described. What remains incompletely characterized are the spectrum of mutations predisposing to azole and/or echinocandin resistance, the role of epigenetic mechanisms, and the virulence of resistant (compared with susceptible) Candida strains in humans. According to our results, lowering the MIC break point for caspofungin resistance in C. glabrata bloodstream isolates to 0.5 mg/L is clinically relevant.
Our study has several limitations. It was a retrospective study performed at a single institution, and our patient population was rather small and selected. Therefore, our observations might not be applicable to different patient groups at risk for serious Candida infections. The number of caspofungin-resistant isolates was small, and we used in vitro caspofungin MIC alone to define echinocandin resistance, without molecular confirmation of underlying mutations. The interlaboratory variability in caspofungin MICs is substantial,[29,30] and there is evidence that micafungin and anidulafungin MICs correlate better with the presence of FKS mutations and clinical outcomes.[15] However, testing the micafungin and anidulafungin MICs of available caspofungin-resistant isolates did not change our conclusions. Moreover, our most striking finding was the high percentage of multidrug-resistant C. glabrata isolates. In a previous study,[20] 100% of such multidrug-resistant isolates had an FKS mutation; in the study reported here, all multidrug-resistant isolates that were available for testing were resistant to 2 echinocandins. Therefore, we believe that the substantial number of multidrug-resistant strains harbored molecular mechanisms of resistance. It should be noted that the reference for assessing sensitivity and specificity of in vitro MICs has been the presence of mutations within the FKS1 and FKS2 hot spot regions. Nevertheless, there is emerging evidence that non–FKS-related mechanisms might be operative or might predispose to the development of echinocandin resistance and even multidrug resistance.[8,23] Recently, a high in vitro caspofungin MIC (≥0.5 mg/L) was shown[17] to have a higher positive predictive value for echinocandin failure than the presence of FKS hot spot mutations, in agreement with our findings and contrary to previously reported findings.[6,31]
In summary, the rate of in vitro caspofungin and multidrug resistance of C. glabrata bloodstream isolates in our patient population is, to our knowledge, among the highest reported. Our findings might indicate a worrisome propensity of C. glabrata strains for multidrug resistance in cancer patients and should prompt awareness of the need for good stewardship of antifungal drugs. Prospective, large-scale clinical registries, with molecular data on mutations that confer resistance to antifungal drugs, are needed.