Onc and Transplant ID: August 2018

What antifungal agent is most effective for primary prophylaxis in patients with hematologic malignancies? This month AAC published a network meta-analysis of 54 trials addressing this question. Thirty-three of the studies were open-label, none were deemed to be at high risk of bias in randomization, and funnel plot and egger graphs did not suggest publication bias. Collectively, the studies enrolled 12832 subjects. Across studies, half the patients received intensive chemotherapy and a quarter received hematopoietic stem cell transplantation. Most of studies enrolled patients with an ANC less than 1000 cells/ul, but the timing of antifungal prophylaxis was inconsistent.

Amphotericin B (liposomal and aerosolized), fluconazole, itraconazole, voriconazole, posaconazole, and micafungin all reduced the incidence of invasive fungal infection (IFI), with RRs ranging from 0.19 (posaconazole) to 0.51 (fluconazole). Oral polyene, ketoconazole, caspofungin, and amphotericin B lipid complex were not associated with reductions in IFI versus placebo, and there were no studies using isavuconazole. In subgroup analysis examining reductions of invasive aspergillosis, posaconazole was again the superior choice (RR 0.13 versus placebo). In subgroup analysis restricted to proven IFI, only fluconazole, itraconazole, posaconazole, and micafungin demonstrated reduction of IFI versus placebo (RR 0.14 to 0.54), and again with posaconazole was the most effective agent. Figure 5 of this paper is worth a look; the authors present a nice scatterplot showing each drug’s efficacy in preventing overall versus proven fungal infection.

With regards to all-cause mortality, in a total 38 studies (n=8447) none of the drugs demonstrated reduced death versus placebo, though primary prophylaxis with liposomal amphotericin had the strongest trend toward statistical significance (RR 0.44; CI 0.14-1.39). The period across which studies measured mortality (i.e. survival to discharge? 30-day? 90-day? 1-year?) was not given in the main text, which I thought was a shame – because if antifungal prophylaxis extends survival by preventing IFI without preventing long-term mortality due to leukemia, that may still be a worthy goal.

My take-home message from the paper is that posaconazole was consistently the most effective choice for primary prophylaxis of IFI in patients with hematologic malignancy. However, most of the other triazoles, micafungin, and liposomal amphotericin were also effective. 29866872

Incidentally, new European guidelines for primary antifungal prophylaxis in hematologic malignancy were published in JAC this month. They still suggest fluconazole can be used in induction chemotherapy for AML or MDS, recommend combining fluconazole with aerosolized amphoterin B in such patients at high risk of invasive mold disease, and recommend fluconazole alone for patients undergoing allogenic HSCT at low risk of invasive mold infection. However, for patients at high at risk of invasive mold infection, or in centers where the rate of invasive mold disease exceeds 8%, these guidelines recommend posaconazole  as the drug of choice. 30085172

Here’s a nice multicenter description of toxoplasmosis and its management in hematologic stem cell and solid organ transplant recipients. The authors worked with 46 medical centers from 11 countries across Europe to survey their treatment practices and then retrospectively study cases of toxoplasmosis in transplant patients over a 5-year period. During this period, the centers collectively performed 2257 hematologic stem cell, 2556 kidney, 1455 liver, and 394 heart transplants.

A survey of the centers indicated that the majority performed serologic screening for toxoplasmosis in all types of solid organ transplant as well as allogenic HSCTs, whereas screening practices for autologous HSCT were more varied. All centers prescribed trimethoprim-sulfa for allogenic HSCT recipients, usually for 6-12 months; 73% of centers also gave TMP/SMX prophylaxis for autologous HSCT, usually lasting 3-6 months. For heart transplant recipients, 92% of centers prescribed prophylaxis, though durations varied from 3 months to lifelong; 83% of kidney and 53% of liver patients received TMP/SMX prophylaxis for periods ranging from 3-12 months, although in these cases the indication was generally prevention of Pneumocystis pneumonia.

During the 5-year period, the 46 medical centers reported a total 87 cases of Toxoplasma infection in their transplant recipients: 58 cases (67%) occurred in allogenic HSCT recipients, 12 cases (14%) in heart recipients, 9 cases (10%) in kidney recipients, and 8 cases (9%) in liver recipients. Comparing these numbers to the to the numbers of each transplant performed, we see that the incidence of toxoplasmosis is highest in allogenic HSCT and heart transplant recipients (1 in 19 and 1 in 32, respectively), significantly lower for kidney and liver transplant recipients (1 in 285 and 1 in 181), and negligible for autologous HSCT recipients.

Pulmonary and ocular disease were the most common presentations except in kidney transplant recipients, who most often had undifferentiated fever or asymptomatic infection. PCR was used to establish the diagnosis in 89% of cases and was positive in 100% of cases with CNS or pulmonary involvement. When toxoplasmosis occurred, mean time from transplantation to diagnosis was shorter in patients who were seropositive pre-transplant (<4mo after transplant versus >4 years after transplant for seronegative recipients), and these patients were less likely to survive to 6 months (33% versus 78-92%). Of the transplant recipients who developed toxoplasmosis, allogenic HSCT and liver recipients were least likely to survive to 6 months (38% and 50% versus 89-100% for kidney and heart recipients). CNS and pulmonary disease had the lowest rates of survival (38% and 50%, respectively). 30014843

Watch out for immune-mediated graft dysfunction after treating Hepatitis C infection in liver transplant recipients. Such inflammatory reactions had been described with interferon-based treatment of HCV in the past, and this paper from the American Journal of Transplantation shows that they also occur after DAA-based therapy. The authors performed a multicenter study of liver allograft recipients who subsequently underwent DAA treatment of their HCV infections, comparing those who did versus did not develop immune-mediate graft dysfunction (IGD). The incidence of IGD in the cohort was 3.4%, occurred a mean 113 +/- 84 days after completion of DAA therapy, and lasted an average of about 2 months (IQR 31-126 days). IGD was associated with higher rates of hospitalization and infection after HCV treatment, but only one patient in the cohort died (0.1% of the 978 patients treated for HCV) and none had allograft loss. In multivariate analysis, transaminitis during or soon after DAA therapy predicted subsequent IGD.

To summarize, DAA-associated IGD is a rare complication of modern HCV treatment that occurs a few months after treatment and is predicted by transaminitis during or soon after DAA therapy. While a third of cases require hospitalization, with appropriate management the long-term prognosis of IGD is good. 30075485

The addition of sulfamethoxazole restores antifungal activity of voriconazole and itraconazole against Candida auris. I’ve placed this article in the oncology and transplant ID section because I think that’s the audience for whom it’s most useful. C. auris is emerging nosocomial pathogen that can be resistant to azoles, echinocandins, and amphotericin (AKA all of the antifungals we have), and up to 60% of patients who develop infection with this organism die. While it’s just in vitro data, here’s some badly needed good news. Sulfamethoxazole (SMX) exhibits syngergistic antifungal activity with azoles, and particularly with voriconazole and itraconazole, against C. auris. The combination of SMX and voriconazole restored voriconazole’s antifungal activity in 3 of 8 resistant isolates, and the combination of SMX and itraconazole restored itraconazole’s antifungal activity in 3 of 4 resistant isolates. Whether this combination is synergistic for an isolate appears to depend on the mechanism of azole resistance: if an isolate has mutations affecting the azole’s site of action, the combination works, whereas if the isolate has resistance mediated by hyperactive efflux pumps, adding SMX has no effect.

In a nematode model of infection using one of the synergy-susceptible C. auris isolates, adding SMX to voriconazole improved survival by 70%. I know this isn’t the sort of science that usually has a direct influence on patient care, but in the case of C. auris I think we need all the help we can get. 30145250