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Associate Professor and Chair, Department of Clinical Sciences and Administration, College of Pharmacy, University of Houston, Houston, TX
Clinical Coordinator, Department of Pharmacy, St. Luke's Episcopal Hospital, Houston, TX
PharmD Student, Department of Clinical Sciences and Administration, College of Pharmacy, University of Houston
PharmD Student, Department of Clinical Sciences and Administration, College of Pharmacy, University of Houston
Professor, School of Public Health and Baylor College of Medicine, University of Texas—Houston; Chief of Internal Medicine, St. Luke's Episcopal Hospital
Reprints: Dr. Garey, Texas Medical Center, University of Houston College of Pharmacy, 1441 Moursund St., Houston TX 77030, fax 713/795-8383, kgarey{at}uh.edu
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DATA SOURCES: A literature search was performed using PubMed (1996–January 2008), abstracts from the International Conference on Antimicrobial Agents and Chemotherapy (September 2007), the Infectious Diseases Society of America (October 2007), Salix Pharmaceuticals Web site (January 2008), ActivBiotics Web site (January 2008), Google Scholar, and searches of selected bibliographies using the terms rifamycin, ansamycins, rifampin, rifabutin, rifampicin, rifaximin, rifalazil, Clostridium difficile, C. difficile, and CDAD.
STUDY SELECTION AND DATA EXTRACTION: In vivo and in vitro studies investigating the use of rifamycins for CDAD were selected, along with all clinical trials using rifamycins in patients with CDAD.
DATA SYNTHESIS: Nine studies totaling 890 isolates were identified that investigated the in vitro susceptibility of rifampin (6 studies), rifaximin (3 studies), and rifalazil (2 studies). Rifamycins consistently displayed potent activity against tested strains, although strains with decreased susceptibility have been identified. Six published clinical studies involving 81 patients have investigated the use of rifamycins for the treatment of CDAD. These have generally been small studies, although initial positive clinical results have been reported on the use of rifamycins for recurrent CDAD.
CONCLUSIONS: Preliminary data support the use of rifamycins for treatment of CDAD. With the increased incidence and severity of CDAD, further investigation into this drug class as a treatment regimen for CDAD is warranted.
Key Words: Clostridium difficile diarrhea, rifamycin
Published Online, April 22, 2008. www.theannals.com, DOI 10.1345/aph.1K675
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
ACPE UNIVERSAL PROGRAM NUMBER: 407-000-08-011-H01-P
The rifamycin, (or ansamycin) class of antibiotics targets the bacterial DNA-dependent RNA polymerase and includes currently available antibiotics such as rifampin, rifabutin, rifapentine, the newly approved antibiotic rifaximin, and the new investigational agent rifalazil, also known as KRM-1648. Rifampin has been suggested as a potential adjuvant agent for treatment of recurrent CDAD, but the potential use of rifamycins for treatment of CDAD has not been reviewed.4 The purpose of this article is to review the literature on the use of the rifamycin class of antibiotics for the treatment of CDAD, with emphasis on comparison of the activity of these drugs with each other and/or with the 2 most widely used antibiotics in treatment of CDAD, metronidazole and vancomycin.
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RIFAMPIN
Rifampin was found to be the most active among 32 antibiotics tested
against 40 C. difficile isolates collected primarily from patients
with pseudomembranous colitis (PMC) from various parts of the
US.12 Using
microtiter methods, 73% and 98% of the isolates were susceptible to rifampin
at concentrations of 0.06 µg/mL or less and 2 µg/mL, respectively. On
the other hand, 30% and 90% of the isolates were susceptible to metronidazole
at concentrations of 0.25 and 0.5 µg/mL, respectively. The minimum
inhibitory concentrations (MICs) for vancomycin were much higher, with 70% and
100% of the isolates susceptible at vancomycin concentrations of 2 and 4
µg/mL, respectively. The in vitro development of resistance to the various
antibiotics was also studied against 10 of the isolates using the broth tube
dilution method (with successive transfers every 24 hours after anaerobic
incubation at 37 °C for 18–20 h). Resistance was evaluated based on
the terminal/initial MIC ratio after 7 successive transfers. Very low
resistance to vancomycin was observed (terminal/initial MIC ratio 1.9) and
resistance to metronidazole developed slowly (mean terminal/initial MIC ratio
38.5). However, development of resistance to rifampin was observed (mean
terminal/initial MIC ratio 2052). Synergy (defined as 
4-fold reduction in
the MICs of both agents when combined) studies were also carried out using the
checkerboard methodology. Synergy against 68% (27/40) of the strains tested
was observed when rifampin was combined with vancomycin. However, the
combination of rifampin and metronidazole was not synergistic and, in fact, an
antagonistic effect was observed for 30% (3/10) of the isolates tested.
Trends in susceptibility patterns were studied by investigators in France and Belgium using 100 C. difficile isolates collected in 1991 and 98 isolates collected in 1997.13 The MICs for 8 antibiotics, including rifampin, metronidazole, and vancomycin, were determined. The agar microdilution and E-test methodologies were used to determine susceptibilities to metronidazole and vancomycin, while ATB ANA strips were used to determine susceptibilities to rifampin. The MIC50 and MIC90 values for rifampin were not reported. However, decreased susceptibility to rifampin was observed, with 22.7% of the strains having MICs 4 µg/mL or more. Nevertheless, there were fewer strains with that MIC level in the 1997 than in the 1991 strains (7.1% vs 38%, respectively). The reported MIC50 and MIC90 for vancomycin for both the 1991 and 1997 isolates were 1 and 2 µg/mL, respectively. For the 1991 isolates, the MIC50 and MIC90 for metronidazole were 0.25 and 2 µg/mL, whereas for the 1997 isolates the corresponding values were 0.25 and 0.5 µg/mL. Thus, there was no change in the susceptibility patterns for vancomycin, while there was a trend for increased susceptibility to metronidazole.
The in vitro susceptibility of 49 C. difficile isolates to 6 antibiotics, including rifampin, vancomycin, and metronidazole, was studied at a tertiary care medical center in Israel between 2003 and 2004.7 C. difficile isolates were obtained from hospitalized patients admitted during a 6-month period and tested using the disc diffusion method and E-test. Ninety-four percent (46/49) of the isolates were found to be sensitive to all 6 antibiotics tested, including rifampin. For these isolates, the rifampin MIC50 and MIC90 were 0.002 µg/mL and 0.19 µg/mL, respectively. For the same isolates, the MIC50 and MIC90 were 0.023 and 1 µg/mL for vancomycin, and 0.032 and 0.125 µg/mL for metronidazole, respectively. Three of the isolates showed resistance to at least one of the antibiotics tested. One of these isolates was resistant to rifampin, with an MIC greater than 32 µg/mL. This was reportedly the first human C. difficile isolate found to be resistant to rifampin.
A study performed in the US investigated the in vitro susceptibility to, and synergy of, rifampin, vancomycin, and metronidazole for 55 C. difficile clinical isolates collected from patients from medical centers in Michigan and Delaware.6 MIC testing was performed using the agar dilution method and synergy studies were performed using the checkerboard methodology.14 Actual MIC50 and MIC90 values were not reported; however, 89% of the 55 isolates tested were inhibited by rifampin at a concentration of 0.001 µg/mL, which was much lower than the 100% inhibitory concentration for vancomycin (1.6 µg/mL; 47 isolates tested) and the 93% inhibitory concentration for metronidazole (0.8 µg/mL; 42 isolates tested). There was no synergy when rifampin was combined with vancomycin, and only partial synergy (38%; 16/42 of the strains tested) was observed when rifampin was combined with metronidazole. No resistance to rifampin, vancomycin, or metronidazole was reported.
The in vitro susceptibility of C. difficile to rifampin, metronidazole, vancomycin, and 12 other antibiotics was determined for 258 clinical isolates from a 2004 outbreak in Quebec, Canada, using the agar dilution method.8 Strains were characterized as the hypervirulent strain (NAP1), NAP2, and other non-NAP1 and non-NAP2 strains using pulsed field gel electrophoresis. The majority of the strains isolated were of the NAP1 or NAP2 types and were all found to be susceptible to rifampin, vancomycin, and metronidazole. The MIC50 and MIC90 for rifampin were both 0.06 µg/mL or less, which were lower than the MIC50 and MIC90 for vancomycin (both 1 µg/mL) and metronidazole (0.25 and 0.5 µg/mL, respectively).
RIFAXIMIN
A study performed in Italy investigated the in vitro susceptibility and
potential for resistance of rifaximin, metronidazole, and vancomycin against
93 C. difficile clinical isolates obtained from inpatients at various
institutions.10
The MIC50 and MIC90 for rifaximin were
0.004 and 128 µg/mL, respectively, compared with vancomycin (1 and 2
µg/mL, respectively) and metronidazole (0.125 and 0.25 µg/mL,
respectively). Determination of spontaneous resistance to rifampin and
vancomycin was determined using broth and agar dilution methods at antibiotic
concentrations corresponding to 2, 4, and 8 times the MIC. Exposure of C.
difficile strains to 2 times the rifaximin MIC elicited spontaneous
emergence of a resistant strain at a rate of 1 x
10–8, which the authors described as low incidence. No
spontaneously resistant mutants were observed at 4 and 8 times the rifaximin
MIC. Spontaneous emergence of resistant mutants to vancomycin was not
observed. Similar experiments were not carried out with metronidazole.
Overall, the authors concluded that rifaximin exhibited potent in vitro
activity, although there was a tendency for spontaneous resistance to develop
at low concentrations of the antibiotic. However, as oral rifaximin is not
absorbed and high concentrations are reached in the
stool,15 the
drug may be efficacious even with isolates that have higher MIC values.
In another study performed in Italy, the in vitro susceptibility to rifampin and rifaximin was investigated using the agar dilution method for 56 C. difficile isolates from hospitalized patients with gastrointestinal (GI) symptoms suggestive of C. difficile infection and from asymptomatic patients who were receiving antibiotics that would put them at risk for acquiring CDAD.11 Although strict MIC50 and MIC90 values were not reported, rifampin was found to inhibit 53.6% and 87.5% of the isolates at concentrations of 1.56 and 100 µg/mL, respectively. However, rifaximin inhibited 55.4% and 89.3% of the isolates at concentrations of 0.39 and 100 µg/mL, respectively. Thus, in this study, both rifampin and rifaximin were highly active in vitro against C. difficile, with rifaximin having greater activity than rifampin.
RIFALAZIL
The in vitro activity of the investigational agent rifalazil has been
investigated in 2
studies.5,9
As part of a study to assess CDAD relapse in a hamster model in comparison
with vancomycin, the in vitro activity of rifalazil was tested versus 31
nonidentical clones of C.
difficile.5
The MIC50 and MIC90 for rifalazil were
0.002 and 0.004 µg/mL, respectively, with only 2 clones requiring MICs
greater than 0.5 µg/mL. Thus, although in vitro susceptibility for
comparator antibiotics was not determined in this study, rifalazil exhibited
potent activity against C. difficile. In a larger study, the in vitro
activities of 15 antimicrobial agents, including rifalazil, rifaximin,
metronidazole, and vancomycin, were tested against 110 toxigenic isolates of
C. difficile collected from 1983 to 2004 at various sites in the US
as well as Europe and
Argentina.9
Of all the antibiotics tested, rifaximin and rifalazil showed the greatest
activity, with MIC50 and MIC90 values of
0.0075 and 0.015 µg/mL, respectively, for rifaximin and 0.0075 and 0.03
µg/mL, respectively, for rifalazil. These MIC50 and
MIC90 values were much lower than those found for vancomycin
(1.0 µg/mL for both), metronidazole (0.125 and 0.25 µg/mL,
respectively), nitazoxanide (0.06 and 0.125 µg/mL, respectively), OPT-80
(0.125 µg/mL for both), and ramoplanin (0.25 and 0.5 µg/mL,
respectively). Three of the 110 C. difficile strains exhibited MICs
greater than or equal to 256 µg/mL for both rifalazil and rifaximin,
suggesting the potential of in vitro resistance to these antibiotics. Two of
these resistant strains were obtained in 1998 from patients in Argentina, with
the remaining strain isolated in 1995 from a patient in Chicago.
In summary, 8 publications have shown that the in vitro potencies of rifamycin antibiotics are at least comparable to, or more potent than, metronidazole, vancomycin, and other comparator antibiotics. However, 3 of the studies reported strains with elevated MIC values to rifamycins. Whether the more widespread use of rifamycins as sole treatment for CDAD will lead to increased resistance remains to be determined.
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Rifampin is available for oral and parenteral administration. It is readily absorbed from the GI tract following oral administration and achieves serum peak concentrations in the range of 8–20 mg/L after a 600-mg oral dose.16 Rifampin is approximately 80% serum protein bound, and its plasma clearance is largely through hepatic conversion to an active metabolite. The drug undergoes extensive enterohepatic recirculation and is largely excreted via fecal elimination after oral administration. However, studies quantitating fecal concentrations of this drug in humans following typical oral doses are lacking. Rifampin is also a potent inducer of CYP3A4 and is thus associated with multiple drug interactions. It is almost never used alone due to the high tendency for development of resistance to this antibiotic.
Rifaximin is available only for oral administration. It possesses many of the qualities of an ideal agent for treatment of CDAD. This rifamycin has been modified with a benzimidazole ring, which makes it virtually nonabsorbable from the GI tract. A number of pharmacokinetic studies including healthy volunteers and patients with ulcerative colitis have shown that the plasma concentration of this drug following either a single 400-mg oral dose or a 200-mg twice daily oral dose for 10 days is virtually undetectable.20-22 Stool concentrations of rifaximin following a 200-mg twice daily oral dose for 3 days were found to be as high as 8000 µg/g of stool.15 This is comparable to stool vancomycin concentrations of 3100 µg/g of stool found in patients with antibiotic-associated PMC who were taking 2-g daily oral doses.23 In contrast, stool metronidazole concentrations of 3.3 µg/g of stool were found in patients with C. difficile colitis who were taking 500-mg twice daily orally.24 Taken together, these results show that the systemic absorption of rifaximin following oral administration is negligible, making it an ideal agent for the treatment of GI disorders. Furthermore, unlike rifampin, rifaximin does not induce cytochrome P450 enzymes.25 Thus, lack of enzyme induction, combined with low systemic absorption, significantly decreases the potential for drug–drug interactions and untoward adverse effects. Lastly, although MICs greater than 256 µg/mL have been observed for some C. difficile strains, the high drug concentrations achieved in the feces following oral administration and the low rate of selection of resistant mutants at 8 times the MIC indicate that it is possible that resistance may not be clinically significant.9,10
Rifalazil is a newly developed oral semisynthetic rifamycin not yet
commercially available. It has been modified with a benzoxazine ring, giving
it a long half-life that may permit once-daily oral
dosing.18
Rifalazil is absorbed via the GI tract and its bioavailability after oral
administration decreases as the dose is increased, likely due to its low water
solubility in the intestinal water contents. Animal studies have shown that,
once it is absorbed, rifalazil is highly protein bound
(
99%).26
Although active metabolites have been identified, rifalazil is primarily
eliminated unmetabolized by biliary excretion via the GI tract. Unlike with
rifampin, studies in rats and dogs have shown that rifalazil does not induce
CYP3A4.27
Thus, all 3 rifamycins achieve high colonic concentrations of the active drug
due either to the fact that they are not absorbed (rifaximin) or that they
undergo enterohepatic circulation, leading to biliary excretion of active drug
into the GI tract (rifampin and rifalazil).
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Rifaximin has also been studied in the CDAD hamster model for prophylaxis, treatment, and relapse prevention.28 In this study, hamsters were administered vancomycin 50 mg/kg; rifaximin 25, 50, or 100 mg/kg; or vehicle (4.5% sodium dodecyl sulfate in buffer) by gavage once daily for 5 days. The experimental design was similar to the one described above except that a lower vancomycin dose was used and the hamsters were infected either with a reference toxinogenic C. difficile strain or the hypervirulent toxinotype III (BI17-6443) strain and were observed for a maximum of 27 days. Also, the rifaximin MIC for the C. difficile strains used was not reported. All vehicle-treated hamsters either died or had to be killed within 48 hours of C. difficile infection. Following infection with the reference toxigenic strain, both vancomycin and rifaximin had a significant beneficial effect on survival rates in the prophylaxis group at 7 days postinfection. The effect of rifaximin on survival rates was dose dependent (80%, 70%, and 60% survival for the 100-, 50-, and 25-mg/kg doses, respectively). The survival rates were higher when treatment was initiated one day postinfection (treatment group) with the reference toxigenic strain (100% survival for vancomycin and rifaximin at the 2 higher doses and 80% for rifaximin at 25 mg/kg).
Prevention of recurrence using vancomycin or rifaximin was also studied with both the reference toxigenic and the hypervirulent C. difficile strains.28 Following infection with the reference toxigenic strain, none of the rifaximin-treated animals relapsed, compared with a relapse rate of 25% for the vancomycin-treated animals. In contrast to the above findings with the toxigenic reference strain, none of the hamsters treated with either vancomycin 50 mg/kg or rifaximin 100 mg/kg in either the prevention or treatment groups relapsed, and all survived to the end of the observation period. As the authors suggested, this unexpected finding may reflect species-specific differences with regard to CDAD infection. Histological studies were carried out only with the toxigenic reference strain, and the findings were similar to those of the rifalazil study in that rifaximin was more effective in preventing mucosal injury compared with vancomycin. Thus, this study suggests that administration of rifaximin once daily for 5 days may be equal to vancomycin for CDAD prophylaxis and treatment and perhaps superior to prevent relapse in the animal model.
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Buggy et al.30 reported a case series of 7 patients who had experienced multiple relapses of CDAD. Four patients had documented pseudomembranes by endoscopy. Six patients had been treated with oral vancomycin for previous episodes, and 1 patient had received treatment with oral vancomycin, metronidazole, and bacitracin. All patients also had prior non-CDAD antibiotic exposure that included erythromycin, clindamycin, trimethoprim/sulfamethoxazole, penicillins, or cephalosporins. These patients were subsequently treated for CDAD with vancomycin and rifampin. Follow-up consisted of stool cultures obtained before combination therapy and at 10, 20, 30, 60, and 90 days thereafter, along with a diary of symptoms that was maintained by all patients. All patients had cessation of abdominal pain within 24 hours and normalization of stool by day 3, on average. All stool cultures initially became negative but were then uniformly positive at 1- to 2-month follow-up visits. Although one patient had an antibiotic-associated symptomatic relapse, which responded to oral bacitracin, the other patients remained asymptomatic despite testing positive for C. difficile toxin. Biotyping of strains from 5 of the 7 patients revealed that 3 of these patients were reinfected with the same strain, while the other 2 were reinfected with a new strain. No resistance was observed in cultures obtained after treatment with rifampin.
Two case series have investigated the use of rifaximin for treatment of recurrent CDAD.31,32 Johnson et al.32 published a case series of 8 females with a minimum of 4 prior episodes of symptomatic recurrent CDAD. Prior episodes had been treated with a variety of regimens including metronidazole, vancomycin, vancomycin and rifampin, tapering/pulsed doses of vancomycin, or Saccharomyces boulardii. The authors did not describe other prior non-CDAD antibiotic exposures. All patients were immediately given a 2-week course of rifaximin (range 400–800 mg daily given in 2 or 3 divided doses) when asymptomatic following their last course of vancomycin (dose and duration not stated). Follow-up range was 51–431 days. Seven patients experienced no further diarrhea; 1 patient had one relapse 10 days after completing rifaximin therapy. This patient responded to a second 2-week course of rifaximin monotherapy and did not experience any further diarrhea episodes after 9 months of follow-up. The same patient had stool cultures performed before her first and second course of rifaximin which showed infection by the same strain. However, the MIC had increased from 0.0078 µg/mL for the pretreatment isolate to 256 µg/mL for posttreatment isolate (following the second course of rifaximin), indicating the possibility for emergence of rifaximin-resistant mutants.
The second case series involved 6 patients who had experienced 1–4 prior episodes of symptomatic recurrent CDAD despite treatment with various antibiotic regimens.31 A variety of CDAD therapies had been tried for these patients, including oral metronidazole, oral vancomycin, combined oral vancomycin with intravenous metronidazole, combined oral vancomycin with oral nitazoxanide and intravenous metronidazole, and nitazoxanide monotherapy. Prior non-CDAD antibiotic exposure was not discussed. In contrast to the above study, the patients were treated while still symptomatic (Table 2). Five patients who received the tapered rifaximin regimen did not experience further CDAD recurrences during the follow-up period ranging from 54 to 398 days. The sixth patient died from underlying cardiorespiratory failure unrelated to CDAD, still with persistent diarrhea. However, although this patient's stools were initially positive for C. difficile toxin, 4 separate posttreatment stool cultures tested negative for C. difficile.
Clearly, large, double-blind randomized trials are needed; however, these 2 case series studies provide preliminary evidence for the effectiveness of rifaximin in the treatment of recurrent CDAD. Nevertheless, the potential for emergence of rifaximin resistance will require monitoring as the use of rifaximin becomes more prevalent.
Two clinical studies have investigated the use of rifaximin or rifampin for CDAD treatment.33,34 In 1990, a small open-label, head-to-head, trial of rifaximin versus vancomycin was conducted.33 All of the patients given vancomycin and 9 of 10 given rifaximin experienced complete resolution of symptoms. Duration of diarrhea was similar in both groups; however, mean elimination of toxins ± SD was significantly longer in the rifaximin-treated group (8.1 ± 1.79 days) compared with the vancomycin-treated group (4.8 ± 1.48 days). Finally, the efficacy of oral metronidazole with or without oral rifampin was studied in a small trial for treatment of primary CDAD infection.34 Exclusion criteria included prior use of CDAD antibiotics (>24 h) and previous CDAD diagnosis. Prior non-CDAD antibiotic use was not discussed. Patients were randomly assigned to receive metronidazole monotherapy or metronidazole combined with rifampin and were treated for 10 days. The follow-up period was 30 days from completion of treatment and included testing for C. difficile toxins A and B. An intent-to-treat analysis was used. Seven patients did not complete the 10-day regimen (treatment arms not reported).
The results showed no statistically significant differences between the 2 groups in terms of time to clinical improvement and time to first relapse. Although fewer patients in the combination metronidazole and rifampin group had relapsed by the end of the observation period compared with the metronidazole monotherapy group, the difference was not statistically significant. Furthermore, of the 7 patients who died within 40 days of enrollment, 6 were in the combination treatment group. The study was powered at the 80% level and required 100 subjects to detect a 20% difference in relapse rates. However, the study was stopped early because the investigators determined that even if they recruited the entire cohort, it was unlikely that a significant difference between the 2 treatment arms would be found. It is interesting that the majority of subjects were inpatients and yet they still had a number of drop-outs or discontinuations.34
In summary, 2 animal studies with rifalazil and rifaximin in a CDAD hamster model have demonstrated the potential for rifamycins to prevent CDAD relapse. Three case series, 1 with rifampin and 2 with rifaximin, have shown promise using rifampin in combination with oral vancomycin, rifaximin after the use of oral vancomycin in asymptomatic patients, or rifaximin after conventional therapy in symptomatic patients to prevent further relapse in those with recurrent CDAD. One small clinical study suggests that rifaximin is not superior to vancomycin as first-line therapy for treatment of CDAD. Finally, a small study with 39 patients showed that combination therapy with metronidazole and rifampin provided no benefit over monotherapy with metronidazole in patients with primary CDAD. This finding is consistent with prior in vitro synergy studies showing either only partial synergy for the combination of metronidazole and rifampin or antagonistic effects.6,12
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A recent pharmacokinetic study assessed the safety of oral rifalazil in healthy male volunteers.40 In this randomized, 3-way crossover design study, subjects received three 25-mg doses separated by 3- or 4-week washout periods. In general, rifalazil was well tolerated with no serious adverse events reported. Backache and headache (25% and 17%, respectively) were the most commonly reported adverse effects. However, the safety and tolerability of rifalazil at higher doses and frequency of administration remain to be determined.
The Food and Drug Administration–approved label for rifaximin lists primarily GI adverse effects, along with headache and pyrexia. In a double-blind, randomized, dose-finding study in subjects with hepatic encephalopathy, rifaximin was found to be well tolerated.41 Subjects received 600, 1200, or 2400 mg of rifaximin daily in divided doses for 7 days, with no consistent pattern of adverse effects. In a double-blind, randomized, placebo-controlled study of rifaximin for the prevention of traveler's diarrhea, rifaximin was also found to be well tolerated.15 There was no statistically significant difference in adverse effects or laboratory abnormalities between subjects receiving rifaximin (200 mg once, twice, or 3 times daily for 2 wk) and those receiving placebo. In general, it has been difficult to separate the adverse effects of rifaximin reported by patients from disease-related symptoms.
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