New Weapon in the Fight Against C.Diff

Introduction

Throughout my medical school career, there are many things, both good and bad which I will never forget, among them is the pungent odor of a C.difficile infection. Its an unmistakable stink which brings back memories of awkwardly trying to write a note or perform a physical exam while wearing one of those big yellow isolation gowns. C. diff's unshakable presence in our hospitals is only expected to get worse as our careless over-use of antibiotics creates more opportunities for c.diff to out compete the normal colonic flora.

Traditionally, C.diff infections have been treated with Flagyl firstline and Vancomycin for those who failed Flagyl or have fulminant disease. However, due to increasing resistance to Flagyl, Vancomycin is rapidly becoming the only effective drug for many patients. However, even Vancomycin sometimes cannot eliminate this nasty critter causing patients to relapse almost as soon as they leave the hospital. The result is chronic, uncontrollable malodorous diarrhea that can destroy a patient's quality of life and create nightmares for hospital infection control and cost billions of dollars for our health care system.

However, hope is on the horizon with a new antibiotic -Fidaxomicin, which has recently completed phase 3 trials. Fidaxomicin is a macrolide antibiotic produced by Optimer Pharma which has shown higher in vitro activity against c.diff than vancomycin. In an article published in February of 2011 in the NEJM, Louie et al. present results from a phase III trial involving 629 patients.

Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364(5):422-31.Methods: Patients were selected whom had diarrhea for 24 hours and either c.diff toxin A or B.

Patients could have received up to 4 doses of Flagyl or Vanc but no other therapy in the 24 hrs before randomization. Patients with fulminant c.diff or >1 recurrence of c.diff in the past 3 month were excluded. Patients were randomized to a 10 day course of either 200mg of Fidaxomicin q12h or 125mg of Vanc q6h. Patients were stratified according to whether this is their first or second episode of c.diff. All patients were followed for at least 28 days following the end of treatment.

Outcomes measured were:

1. clinical cure defined as cessation of diarrhea and no need for additional treatment.

2. Treatment failure was defined as continuation of diarrhea or need for additional therapy.

3. Global cure was defined as no recurrence within the 28 day follow up after end of therapy.

Patients were analyzed as modified intention to treat if they took at least one dose of medication.

Results:

A total of 596 patients were analyzed in the modified intention to treat analysis of which 92% actually adhered to the protocol. They did not differ in baseline characteristics.

Figure 1. mITT=modified intention to treat, PP=per protocol.

As shown in figure 1. Fidaxomicin was as equally efficacious as vancomycin in achieving clinical cure (resolution of diarrhea, no need for additional Rx). However, it achieved a 40% relative reduction in recurrence compared to vancomycin (absolute rate reduction of recurrence from 25% to 15%) (p=0.005).

s shown in Figure 2, in subgroup analysis, Fidaxomicin was superior to or as equally efficacious as Vancomycin at controlling C.diff recurrence in almost every subgroup save for 1. This subgroup comprised of patients with a certain genotype of c.diff known as NAP1/B1/027. For this group, fewer patients had relapse of c.diff after vancomycin treatment (21%) compared to fidaxomicin (27%) however this difference was not statistically significant.

Figure 2.

Safety wise, the rate of adverse and serious adverse reaction was similar in patients treated with Fidaxomicin or Vancomycin.

Discussion:

C.diff is a particularly difficult disease to treat (hence the name) because it is resistant to so many different antibiotics and because even successfully treated patients recur as much as 30% of the time within 60 days. More worryingly, strains of c.diff are becoming resistant to our two current standards of care: Vanc and Flagyl.

Louie et al. show in this study that Fidaxomicin is as efficacious and safe as vancomycin in treating acute infections of c.diff and perhaps more effective at eliminating recurrences. In addition, Fidaxomicin was previously shown to have poor system absorption through the GI tract, a positive attribute because it increases the concentration of the drug which actually reaches the colon after oral administration and also decreases systemic side effects.

The only wrinkle in all of this good news is that the 36% of patients with an aggressive strain of c.diff BI/NAP1/027 do not seem to obtain any additional reduction in recurrence with Fidaxomicin as compared to vanc. This is worrying because patients with this strain of c.diff is the most in need of a better treatment option.

Overall however, fidaxomicin represents an important addition to our current inventory of Flagyl and Vancomycin for the treatment of c.diff.