Other Emerging Antibiotic Therapies
A number of other antibiotics are undergoing further studies to evaluate their potential for treating or reducing the risk of CDI.
Rifaximin
Rifaximin is a broad-spectrum rifamycin antibiotic that is extremely active against C. difficile in vitro (MIC90 of 0.015 μg/ml against 110 toxigenic strains) as well as against numerous Gram-positive and Gram-negative aerobes and anaerobes, although it does not seem to disrupt the intestinal microflora. A number of small studies have shown clinical improvement in CDI patients treated with rifaximin who failed metronidazole therapy. Mattila et al. recently conducted a retrospective analysis of patients with recurrent CDI who had undergone an average of 4.4 courses of standard antibiotic therapy and subsequently received rifaximin treatment. At 12 weeks after the start of treatment, 53% of patients had not relapsed. Although this study did not include a control group, the results suggest the potential efficacy of rifaximin as salvage therapy for the treatment of recurrent CDI, as the historic recurrence rate for patients with two prior relapses can be up to 65%.
In addition, several studies using rifaximin as a chaser treatment following vancomycin have shown success in patients with multiple recurrences or who failed other treatments. The small and uncontrolled nature of many of these studies, however, made it difficult to provide clear treatment recommendations. In a more recent randomized, double-blind, placebo-controlled study, patients were treated with either a rifaximin chaser or placebo for 20 days after completing standard therapy for CDI. Patients treated with rifaximin (400 mg three times daily) experienced a 21% recurrence rate as compared to 49% in the patients treated with placebo (P = 0.018). Although the use of rifaximin chasers appears to be a promising approach, larger studies are needed to add significance to the results and to optimize the treatment dose. It is also important to consider that rifamycin antibiotics have a high rate of bacterial resistance, which raises the possibility of the development of resistance against rifaximin. Several studies have noted the isolation of C. difficile strains with decreased rifaximin susceptibility from patients who received rifaximin therapy.
Tigecycline
Tigecycline is a broad-spectrum i.v. tetracycline derivative that is active against C. difficile as well as other Gram-positive and Gram-negative microorganisms. Standard dosing is a 100 mg loading dose and subsequently 50 mg i.v. every 12 h. It reaches higher concentrations in the stool than metronidazole and has previously been successful in treating a small number of individual cases of severe and refractory CDI. More recently, El-Herte et al. reported success using combined tigecycline and rifaximin to treat a case of severe CDI. Kopterides et al. reported a case of failed tigecycline therapy, however, and raised concerns about the risk of acquiring tigecycline-resistant microorganisms. In addition, concern has arisen about an increased mortality risk associated with tigecycline use, which resulted in an FDA warning recommending the use of alternative therapies in patients with severe infections. Therefore, tigecycline may have promise in treating severe and refractory CDI, but caution should be used when prescribing off-label. A clinical trial is currently in progress to evaluate the safety and efficacy of tigecycline in patients with mild-to-severe CDI (NCT01401023 ClinicalTrials.gov).
Teicoplanin
Teicoplanin is a glycopeptide antibiotic that is active against C. difficile and other Gram-positive anaerobes. A previous Cochrane review of randomized, controlled trials found that teicoplanin had a cure rate superior to vancomycin for CDI, although the study sample sizes were small (82% bacteriologic cure rate for teicoplanin versus 45% for vancomycin, RR 1.82, 95% CI 1.19–2.78). The European Society of Clinical Microbiology and Infectious Diseases recommends a dose of 100 mg twice daily as an additional option for treatment of CDI, but expense and limited drug availability in the United States have reduced the use of teicoplanin as a therapeutic agent.
Doxycycline
Treatment with doxycycline as part of conventional treatment for other infections has been previously associated with a reduced risk of CDI as compared with other antibiotics. A recent cohort study by Doernberg et al. investigated whether hospitalized patients receiving treatment with ceftriaxone along with doxycycline had a reduced risk of CDI development in comparison to those treated only with ceftriaxone. Results showed that for each day that a patient received doxycycline in addition to ceftriaxone, the risk of developing CDI decreased by 27% (hazard ratio, 0.73; 95% CI 0.56–0.96). This study suggests that doxycycline may have a protective effect against CDI, possibly because of its activity against anaerobic bacteria or reduction of C. difficile toxin production as it inhibits protein synthesis. Further clinical trials are needed to establish this association.
Linezolid
Linezolid is an oxazolidinone antibiotic that has high in-vitro activity against a large number of C. difficile strains and other Gram-positive bacteria. In an in-vitro gut model, linezolid treatment resulted in reduced duration of toxin production and reversible disruption of the normal intestinal microflora. A recent study examined the role of linezolid in preventing the development of CDI in major heart surgery patients treated for ventilator-associated pneumonia. In this retrospective study, patients who did not develop CDI had been treated with more doses of linezolid than patients who did develop CDI (12.4 ± 9.7 defined daily doses versus 6.7 ± 4.0 defined daily doses, P = 0.007). These results are the first to suggest the potential protective value of increased doses of linezolid against development of CDI (hazard ratio = 0.908, 95% CI 0.83–0.99, P = 0.04), although a very specific patient population was studied. More studies are needed in vivo to define the appropriate dosing range for CDI patients and further investigate efficacy.
Nitazoxanide and Amixicile
Nitazoxanide is a thiazolide compound with activity against Gram-positive and Gram-negative anaerobic bacteria. Two randomized clinical trials showed equivalent cure and relapse rates in patients treated with nitazoxanide as compared with metronidazole and vancomycin for primary CDI. Nitazoxanide has also exhibited efficacy in CDI refractory to metronidazole therapy. Thus far, the major barriers to the use of nitazoxanide are expense and the limited extent of data from clinical trials.
In a recent study by Warren et al., the nitazoxanide derivative amixicile was created in an effort to improve the solubility of the compound and enhance the inhibition of pyruvate:ferredoxin oxidoreductase in pathogenic organisms. In a murine model, amixicile was well tolerated and resulted in a greater reduction in mortality on day 12 of treatment after receiving a C. difficile challenge (56% survival) as compared with vancomycin (15% survival, P = 0.0003) and nitazoxanide (22% survival, P = 0.008). These results suggest that amixicile may hold promise for development and future testing in human trials.
LFF571
LFF571 is a semisynthetic thiopeptide and an analogue of the natural thiopeptide GE2270A, and is strongly active in vitro against C. difficile (MIC90 of 0.25 μg/ml for 50 C. difficile strains), most Gram-positive anaerobes, and numerous intestinal anaerobic and aerobic microorganisms. Like fidaxomicin, it has limited activity against Gram-negative anaerobes in vitro, suggesting that the narrow spectrum of activity may be sparing to the normal intestinal flora. Additionally, there has been no noted cross-resistance to other common antibiotics. Ting et al. recently performed a randomized, double-blind, placebo-controlled study in healthy volunteers that showed the drug reaches high fecal concentrations and is well tolerated. Given the promise of this antibiotic for the treatment of CDI, it is currently in phase 2 clinical trials to assess safety and efficacy in patients with moderate CDI (NCT01232595 ClinicalTrials.gov).
CB-183 315
CB-183 315 is a cyclic lipopeptide that is an analogue of daptomycin and is currently undergoing clinical trials to evaluate efficacy against CDI. It has been shown to have good activity against anaerobic Gram-positive bacteria and has greater in-vitro activity against C. difficile isolates as compared to vancomycin and metronidazole, including those isolates with resistance to fluoroquinolones. It is bactericidal against the NAP1 strains. In addition, it has limited activity against the intestinal microbiota and resistance rarely developed in serial passage trials. In a small phase 2 clinical trial, CB-183 315 resulted in lower relapse rates compared to vancomycin. These results suggest that CB-183 315 may be a promising agent for treatment of CDI. A phase 3 trial is currently ongoing to evaluate the efficacy of CB-183 315 as compared to vancomycin (NCT01085591 ClinicalTrials.gov).