Need for Susceptibility Testing of Linezolid
Abstract & Commentary
Synopsis: The study established a policy of routine susceptibility testing of linezolid and quinupristin/dalfopristin isolates of VRE from any sterile site.
Source: Potoski BA, et al. Clinical failures of linezolid and implications for the clinical microbiology laboratory. Emerg Infect Dis. 2002;8:1519-1520.
Linezolid is the first in a new class of antimicrobials known as the oxazolidinones. It is especially useful in treatment of Gram-positive infections caused by vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). However, as reported in this article, 2 patients exhibited strains of linezolid-resistant and possibly linezolid-nonsusceptible bacteria, suggesting the need to routinely perform susceptibility testing of linezolid and even quinupristin/dalfopristin (Synercid) before using.
The first patient was a 47-year-old male who underwent right ankle fusion with nail placement. Six months later the nail was replaced, and a month later the patient developed an ankle hematoma that was drained; the infection was treated with 7 days of cephalexin. Over the following several weeks the infection worsened, the area irrigated and debrided, and the patient discharged with amoxicillin/clavulanate. Gross pus that was obtained at this time was cultured and grew S aureus that was susceptible to vancomycin, trimethoprim/sulfamethoxazole (TMP-SMX) and gentamicin but resistant to all beta-lactams and clindamycin. Susceptibility testing to linezolid was not performed.
The patient was switched from amoxicillin/clavulanate to oral linezolid, 600 mg twice daily. The patient did well after completing a 7-week course of therapy, but 2 days after the linezolid was stopped, nausea, fever, and chills developed, necessitating a resumption of linezolid. The patient soon ended up in the emergency room with a temperature of 103°F and his ankle warm and tender to palpation. Linezolid was stopped and intravenous vancomycin started. The nail was removed, and cultures from the area grew MRSA with the same sensitivities as the previous MRSA isolate. This time susceptibility testing to linezolid was performed and the isolate was susceptible (MIC = 4 ug/mL). After 4 weeks of vancomycin, the patient was placed on oral TMP-SMX for an additional 12 weeks. Six months after therapy he remained asymptomatic.
The second patient was a 41-year-old woman with refractory acute lymphocytic leukemia admitted for an allogeneic bone marrow transplant. Her hospital course was complicated by Klebsiella pneumoniae sepsis, neutropenia, mental status changes, acute renal failure, and respiratory distress. Antibiotics received included imipenem, amikacin, piperacillin/tazobactam, vancomycin, amphotericin B lipid complex, fluconazole, ciprofloxacin, and tobramycin. While on vancomycin, peripheral and central venous catheter blood cultures grew vancomycin-resistant Enterococcus faecium that was also resistant to both ampicillin and penicillin. The vancomycin was stopped and linezolid, 600 mg intravenously every 12 hours, was started. Although linezolid susceptibility testing was ordered, linezolid was started before the results were available. Three days later, the patient died. The susceptibility results showed the isolate was resistant to linezolid by E-test (MIC = 32 ug/mL), and further testing also showed that the isolate exhibited intermediate susceptibility to quinupristin/dalfopristin (MIC = 2 ug/mL).
As a result of the above, Potoski and colleagues established a policy of routine susceptibility testing of linezolid and quinupristin/dalfopristin isolates of VRE from any sterile site. In the case of MRSA, linezolid and quinupristin/dalfopristin testing is only done upon request, due to the high number of isolates and the fact that nonsusceptibility of linezolid to MRSA has been reported only once.
Comment by Thomas G. Schleis, MS, RPh
In an ideal world, no antimicrobial would be initiated until complete culture and sensitivity data were available. Obviously, that is impossible given the laboratory procedural constraints and the need for empirical antimicrobial coverage when there is nothing to culture. The choice of antimicrobial is often made on professional judgment and modified, if necessary, when laboratory data become available.
Linezolid and quinupristin/dalfopristin have given us ammunition in the fight against resistant organisms. Despite this, these 2 case reports demonstrate the need for accurate susceptibility testing before relying upon these agents to treat VRE or MRSA. This is especially true when these agents are used after other agents have failed or in an already-compromised or severely ill patient. Given the continuing development of antimicrobial-resistant organisms, we can never assume that an agent is going to be effective and must always be aware of, and concerned of, resistant bacteria.
What is especially disconcerting is the lack of effectiveness of linezolid in the first patient, even when susceptibility testing appeared to support its use. While only a single case, it raises a number of questions. Was there a sufficient level of antimicrobial at the site of infection? Should the linezolid have been dosed differently based upon individual patient pharmacokinetics? Do we need to collect more pharmacokinetic and pharmacodynamic data regarding linezolid? Certainly, if other case reports were to surface, these concerns would need to be addressed.
While these newer agents can be extremely effective, it appears that we need to be more cautious in how we use them and monitor their effectiveness. The culture and sensitivity testing policy suggested by Potoski et al appears to be a rational first step in improving the process.
Editor’s note—The first case described was one of clinical resistance in the absence of in vitro resistance and was unsurprising given the presence of a foreign body. In the second case, de novo resistance of E faecium caused a lethal infection.
Resistance to linezolid may be induced by serial in vitro passage and is associated with mutation (characteristaly, G2576U in the closed loop of domain V of the 23S ribosomal RNA of the 50S ribosomal subunit). Such resistance occurs at a very low frequency (10-9 to 10-10 in S aureus). Since multiple copies of the encoding gene exist, resistance increases with accumulation of mutations in individual copies. For instance, in a study of serial isolates of S aureus developing resistance during linezolid therapy, an isolate with an MIC of 8 mg/mL had the G2576T mutation in 2 of 6 alleles, while a later isolate with mutations in 5 alleles had an MIC of 32 mg/mL.1
The emergence of resistance in S aureus, E faecalis and E faecium during linezolid therapy has been reported.2-4 Enterococcal resistance to linezolid developed in 9 of 501 (1.8%) during the manufacturer’s compassionate-use program. A protracted course of linezolid therapy has been associated with an increased risk of emergence of resistance in E faecium.5
In addition, the apparent emergence of resistance in E faecium in the absence of prior oxazolidinone exposure has previously been reported.6 This may be the result of nosocomial spread. In one instance, E faecium that was first recovered from a liver transplant recipient was subsequently transmitted to 6 other patients who had not received linezolid.7
While the frequency is low, hospital laboratories must provide timely susceptibility testing of linezolid against relevant bacteria.
Dr. Schleis is Director of Pharmacy Services Infectious Limited Tacoma, WA Section Editor, Pharmacology.
References
1. Wilson P, et al. Linezolid resistance in clinical isolates of Staphylococcus aureus. J Antimicrob Chemother. 2003;51:186-188.
2. Johnson AP, et al. Emerging linezolid-resistant Enterococcus faecalis and Enterococcus faecium isolated from two Austrian patients in the same intensive care unit. Eur J Clin Microbiol Infect Dis. 2002;21:751-754.
3. Auckland C, et al. Linezolid-resistant enterococci: Report of the first isolates in the United Kingdom. J Antimicrob Chemother. 2002;50:743-746.
4. Jones RN, et al. Linezolid-resistant Enterococcus faecium isolated from a patient without prior exposure to an oxazolidinone: Report from the SENTRY Antimicrobial Surveillance Program. Diagn Microbiol Infect Dis. 2002;42:137-139.
5. Pai MP, et al. Risk factors associated with the development of infection with linezolid- and vancomycin-resistant Enterococcus faecium. Clin Infect Dis. 2002;35: 1269-1272.
6. Tsiodras S, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet. 2001;358: 207-208.
7. Herrero IA, Issa NC, Patel R. Nosocomial spread of linezolid-resistant, vancomycin-resistant Enterococcus faecium. N Engl J Med. 2002;346:867-869.
The study established a policy of routine susceptibility testing of linezolid and quinupristin/dalfopristin isolates of VRE from any sterile site.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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