Rifaximin intake leads to emergence of rifampin-resistant staphylococci
Introduction
Foreign body infections account for approximately half of all hospital-acquired infections and staphylococci are the main causative organisms.1 The economic burden of these infections is huge2 and with an annually increasing number of implants it is likely to rise further. Rifampin plays an important role as combination partner in the treatment of staphylococcal foreign body infections.3, 4 Rifampin-based oral step-down therapy for Staphylococcus aureus ostemyelitis has proven to be very efficient,5 and its indications include the treatment of osteomyelitis due to MRSA.6 The advantages of rifampin in these infections include its high level of biofilm activity,7 the prevention of resistance development to fluoroquinolones8 and its excellent availability after oral intake. The latter is important as staphylococcal foreign body infections often require long term treatment. Treatment failure has been associated with rifampin-resistance of staphylococci in prosthetic joint infections9 and cerebrospinal fluid shunt-associated infection.10 It is well known that monotherapy with rifampin leads to rapid development of resistance in staphylococci11 and that a single point mutation is responsible for clinically relevant high-level-resistance.12 Resistance to rifampin renders staphylococcal foreign body infections difficult to treat.Rifampin is closely related to rifaximin in structure,12 which allows the possibility of cross-resistance between these two substances.
Rifaximin is a widely distributed antimicrobial agent used to treat traveller’s diarrhea,13, 14 Clostridium difficile associated diarrhea15, 16 and hepatic encephalopathy.17, 18 It is virtually not absorbed and reaches very high concentrations in the human bowel, where it is active against many enteropathogens.19 When excreted with the stool rifaximin comes in contact with human skin staphylococci.
The development of rifaximin-resistance in staphylococci has already been shown in-vitro20 and spontaneous rifaximin-resistance has also been described.21 The possibility of cross-resistance between rifampin and rifaximin has been discussed,22 but no evidence has been put forward. The aim of our study was to determine whether rifaximin intake leads to the development of rifampin-resistant staphylococci in healthy volunteers.
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Materials and methods
The study was approved by the local ethics committee and was registered at EudraCT (trial number 2008-006382-91, https://eudract.emea.europa.eu/). Twelve healthy volunteers were recruited for the study. Oral and written informed consent was provided. The mean age of the volunteers was 38 years (range 28–59). Nine volunteers were male and three female. Pregnancy was excluded in the female volunteers prior to intake of the drug. Swabs from the hands, lower arms and perianal skin were obtained on
Results
One volunteer had to discontinue the intake of rifaximin because of adverse events on day 2 (diarrhea and nausea). Eleven volunteers completed the study. During the study 739 staphylococcal isolates were obtained (Table 1). The mean number of cumulative isolates per volunteer was 66 (range 49–86), the mean number of cumulative isolates per swab location was 148 (range 126–167) and the mean number of isolates per day was 105 (range 85–118). The number of isolates per volunteer who completed the
Discussion
Our results show that rifampin-resistant strains of human skin staphylococci emerge after oral intake of rifaximin and can still be found nine weeks after discontinuation of intake. These isolates were found on the perianal skin early after discontinuation of rifaximin intake and appeared on the skin of the hands and lower arms later on. The skin of healthy volunteers has already been used as a model for antimicrobial resistance.24, 25 Previously it has been hypothesized that the rapid
Acknowledgements
Christina Strempfl and Bernadette Neuhold provided valuable microbiologial assistance. Rifaximin tablets were supplied by Gebro Pharma GmbH (Fieberbrunn, Austria). No other funding or support was received.
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