Emergence of rifampicin resistance during rifampicin-containing treatment in elderly patients with persistent methicillin-resistant staphylococcus aureus bacteremia
Journal
Journal of the American Geriatrics Society
Journal Volume
58
Journal Issue
5
Pages
1001-1003
Date Issued
2010
Author(s)
Abstract
To the Editor: Rifampicin or gentamicin is frequently combined with a glycopeptide in treating to achieve bactericidal synergy in patients with persistent methicillin-resistant Staphylococcus aureus (MRSA) infection.1-3 The occurrence of nephrotoxicity caused by gentamicin in older adults limits the use of an aminoglycoside in this population.4 Rifampicin has a number of characteristics that make it potentially effective when used in combination with a glycopeptide, including its potent bactericidal activity and penetration into a variety of tissues and compartments, such as bone and cerebrospinal fluid;1-3 but for clinicians who choose rifampicin as a companion agent to glycopeptides for treating persistent MRSA bacteremia, knowledge of the frequency of rifampicin-resistant MRSA emergence and its associated effect on outcome are important. All hospitalized elderly patients (aged ≥65) with persistent MRSA bacteremia who received a rifampicin-containing regimen at National Taiwan University Hospital from 2001 to 2008 were included in this study. Severity of underlying illness was classified according to the McCabe-Jackson criteria.5 Persistent MRSA bacteremia was defined as the isolation of MRSA in blood cultures on 7 or more consecutive days despite glycopeptide (vancomycin or teicoplanin) administration for 5 or more days. MRSA bacteremia was considered nosocomial when it appeared more than 48 hours after admission. Thirty-day mortality was defined as death without clearance of bacteremia or within 30 days after clearance of bacteremia. Mortality was defined as MRSA related if MRSA infection was persistent and no other definite causes of death were found. The minimum inhibitory concentrations (MICs) of rifampicin (purchased from Sigma Chemical Co., St. Louis, MO) for MRSA isolates were determined using the agar dilution method according to the guidelines recommended by the Clinical and Laboratory Standards Institute.5 Isolates that had rifampicin MICs of 1 μg/mL or less were defined as susceptible, 2 μg/mL as intermediate, and 4 μg/mL or more as resistant.6 Nineteen older patients who received a rifampicin-containing regimen for persistent MRSA bacteremia were identified during the study period (Table 1). The mean age was 75.4 ± 9.5; 11 (57.9%) were female. The most common underlying diseases were diabetes mellitus (42.2%), cancer (36.8%), and end-stage renal disease (31.6%). The majority of bacteremias were secondary (n=17), and catheter-related infections were the most common primary foci (n=8), followed by osteomyelitis (n=3) and infective endocarditis (n=2) (Table 1). Of the seven patients with rifampicin-resistant MRSA bacteremia, four had catheter-related infection, and one each had infective endocarditis, osteomyelitis, and urinary tract infection. Patients with emergence of rifampicin-resistant MRSA were older and more likely to have nosocomial infections, although there were no significant differences in clinical characteristics and unfavorable outcomes between patients with and without emergence of rifampicin-resistant MRSA. The MIC ranges of prerifampicin-treatment isolates from all patients were 0.15 to 2 μg/mL, and none of the MRSA isolates were resistant to rifampicin. Rifampicin-resistant MRSA was subsequently isolated from seven (36.8%) patients at a median of 9 days (range 5–18 days) after commencement of rifampicin treatment, and the MICs of rifampicin-resistant MRSA were all greater than 128 μg/mL. Rifampicin is currently the most commonly used agent in oral combination therapy for MRSA infection, but rifampicin resistance usually develops rapidly after mutations altering the β-subunit and limits the value of this agent in the management of MRSA infection.1 This is the first study to demonstrate the emergence of rifampicin resistance in MRSA blood isolates from elderly patients with concurrent use of rifampicin. Overall, seven of 19 patients (36.8%) treated with rifampicin-containing therapy acquired rifampicin resistance in this study, indicating that concurrent usage of rifampicin can rapidly result in the development of rifampicin resistance in MRSA infections, especially in very old patients. These findings are consistent with those of a previous study7 in which emergence of resistant MRSA developed in 13 (30%) of 44 patients receiving vancomycin–rifampicin combination therapy. These results support the need for regular monitoring of rifampicin susceptibility if rifampicin is to be used in combination with glycopeptides for the treatment of MRSA bacteremia. Although patients with development of rifampicin-resistant MRSA infection had a higher mortality rate in this study, this difference was not significant, probably because of the small sample size. Further study with a larger sample size is needed to assess the effect of rifampicin resistance and combination use of rifampicin with glycopeptides on the outcome of patients with MRSA bacteremia. Hepatoxicity occurred during rifampicin use in three (15.8%) patients in this study, including hyperbilirubinemia in two patients and hepatitis in one patient. These findings suggest that rifampicin may cause a much higher incidence of hepatotoxicity in older adults than reported in previous studies of younger adults,8, 9 which found that clinical hepatitis developed in 1.1% (14/1,264) of patients receiving a rifampicin-containing regimen and hyperbilirubinemia in 0.6% of patients. The difference may be attributable to the effects of aging on hepatic function. In addition, the findings of the current study indicate the importance of close monitoring of liver function while using rifampicin for MRSA bacteremia in older adults. In conclusion, treatment with a rifampicin-containing regimen for MRSA bacteremia is likely to rapidly induce rifampicin resistance, especially in very old patients. The higher mortality rate of patients with emergence of rifampicin-resistant MRSA during rifampicin-containing treatment and the higher frequency of hepatotoxicity in patients with current rifampicin usage in MRSA bacteremia warrant clinical attention and further study. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Study concept and design: Lai, Lin, Hsueh. Acquisition of data: Tan, Liao. Analysis and interpretation of data: Huang. Preparation of letter: Lai, Hsueh. Sponsor's Role: None.
SDGs
Other Subjects
rifampicin; teicoplanin; vancomycin; rifampicin; aged; antibiotic resistance; antibiotic sensitivity; bacterium isolation; blood culture; clinical article; controlled study; elderly care; female; geriatric patient; hospital care; hospital infection; human; letter; male; methicillin resistant Staphylococcus aureus infection; minimum inhibitory concentration; mortality; treatment duration; antibiotic resistance; bacteremia; drug effects; isolation and purification; microbiology; penicillin resistance; Staphylococcal Infections; Staphylococcus aureus; very elderly; Aged; Aged, 80 and over; Bacteremia; Drug Resistance, Bacterial; Female; Humans; Male; Methicillin Resistance; Rifampin; Staphylococcal Infections; Staphylococcus aureus
Type
letter