1,3--D-Glucan in Patients Receiving Intravenous Amoxicillin–Clavulanic Acid
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The fungal component 1,3--D-glucan is increasingly used to diagnose opportunistic invasive mycoses in immunocompromised patients.1,2,3 The 1,3--D-glucan assay (Fungitell, Associates of Cape Cod) was recently approved by the Food and Drug Administration. We found that the serum samples from two patients with hematologic conditions were positive for 1,3--D-glucan during treatment with intravenous amoxicillin–clavulanic acid. Serum samples were negative after treatment was discontinued. Neither patient had evidence of invasive fungal disease. Furthermore, 1,3--D-glucan was detected in the amoxicillin–clavulanic acid used to treat these patients.
We then tested 10 serum samples from six patients treated with intravenous amoxicillin–clavulanic acid and found 1,3--D-glucan in 9 (cutoff value, 60 pg per milliliter). The mean level of reactivity (1339±1798 pg per milliliter) was significantly higher than that in serum samples from 10 patients treated with ceftazidime (17.7±26.5 pg per milliliter, P=0.002) and from healthy blood donors (8.0±13.8 pg per milliliter, P=0.001). Serum samples from two of the six patients tested before the intravenous administration of amoxicillin–clavulanic acid were negative for 1,3--D-glucan, but serum samples taken 20 minutes after the end of the infusion were positive (805 and 446 pg per milliliter).
Ten batches of the amoxicillin–clavulanic acid infusion fluid used during this period (including the five batches used to treat the six patients) were positive for 1,3--D-glucan (9414±7774 pg per gram of antibiotic), as opposed to four batches of ceftazidime infusion fluid (10±21 pg per gram of antibiotic, P=0.004). Both drugs were diluted according to standard methods for clinical use, and all diluents (i.e., water and 0.9 percent sodium chloride) were negative for the glucan. A single dose of 1000 mg of amoxicillin plus 200 mg of clavulanic acid contained 2856 to 28,016 pg of 1,3--D-glucan, which is 48 to 467 times the cutoff value in 1 ml of serum.
Serum samples from the six patients treated with intravenous amoxicillin–clavulanic acid also had significantly higher levels of galactofuranose antigens (measured with the use of the Platelia Aspergillus enzyme immunoassay, Bio-Rad Laboratories) than the samples from patients treated with ceftazidime (P=0.003) or samples from healthy blood donors (P=0.009). These components are used for the diagnosis of invasive aspergillosis4 and have previously been reported to be present in piperacillin–tazobactam and amoxicillin–clavulanic acid.5 In addition, we observed no glucan reactivity in five batches of piperacillin–tazobactam (23±26 pg per gram).
These results are highly suggestive of cross-reactivity of the Fungitell assay with amoxicillin–clavulanic acid. Physicians should be aware of the possibility of false positive 1,3--D-glucan results in patients treated with this antibacterial agent. The presence of two different fungal components in the antibiotic provides strong evidence of a fungal origin of the cross-reactive components in the drugs. Given the difficulties encountered in the diagnosis of invasive fungal disease, it would be desirable to eliminate the fungal material from antibiotic agents.
Monique A.S.H. Mennink-Kersten, Ph.D.
Adilia Warris, M.D.
Paul E. Verweij, M.D.
Radboud University Nijmegen Medical Center
6500 HB Nijmegen, the Netherlands
m.mennink@mmb.umcn.nl
References
Obayashi T, Yoshida M, Mori T, et al. Plasma (13)-beta-D-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet 1995;345:17-20.
Ostrosky-Zeichner L, Alexander BD, Kett DH, et al. Multicenter clinical evaluation of the (13) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 2005;41:654-659.
Odabasi Z, Mattiuzzi G, Estey E, et al. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 2004;39:199-205.
Mennink-Kersten MASH, Donnelly JP, Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis. Lancet Infect Dis 2004;4:349-357.
Sulahian A, Touratier S, Ribaud P. False positive test for aspergillus antigenemia related to concomitant administration of piperacillin and tazobactam. N Engl J Med 2003;349:2366-2367.
We then tested 10 serum samples from six patients treated with intravenous amoxicillin–clavulanic acid and found 1,3--D-glucan in 9 (cutoff value, 60 pg per milliliter). The mean level of reactivity (1339±1798 pg per milliliter) was significantly higher than that in serum samples from 10 patients treated with ceftazidime (17.7±26.5 pg per milliliter, P=0.002) and from healthy blood donors (8.0±13.8 pg per milliliter, P=0.001). Serum samples from two of the six patients tested before the intravenous administration of amoxicillin–clavulanic acid were negative for 1,3--D-glucan, but serum samples taken 20 minutes after the end of the infusion were positive (805 and 446 pg per milliliter).
Ten batches of the amoxicillin–clavulanic acid infusion fluid used during this period (including the five batches used to treat the six patients) were positive for 1,3--D-glucan (9414±7774 pg per gram of antibiotic), as opposed to four batches of ceftazidime infusion fluid (10±21 pg per gram of antibiotic, P=0.004). Both drugs were diluted according to standard methods for clinical use, and all diluents (i.e., water and 0.9 percent sodium chloride) were negative for the glucan. A single dose of 1000 mg of amoxicillin plus 200 mg of clavulanic acid contained 2856 to 28,016 pg of 1,3--D-glucan, which is 48 to 467 times the cutoff value in 1 ml of serum.
Serum samples from the six patients treated with intravenous amoxicillin–clavulanic acid also had significantly higher levels of galactofuranose antigens (measured with the use of the Platelia Aspergillus enzyme immunoassay, Bio-Rad Laboratories) than the samples from patients treated with ceftazidime (P=0.003) or samples from healthy blood donors (P=0.009). These components are used for the diagnosis of invasive aspergillosis4 and have previously been reported to be present in piperacillin–tazobactam and amoxicillin–clavulanic acid.5 In addition, we observed no glucan reactivity in five batches of piperacillin–tazobactam (23±26 pg per gram).
These results are highly suggestive of cross-reactivity of the Fungitell assay with amoxicillin–clavulanic acid. Physicians should be aware of the possibility of false positive 1,3--D-glucan results in patients treated with this antibacterial agent. The presence of two different fungal components in the antibiotic provides strong evidence of a fungal origin of the cross-reactive components in the drugs. Given the difficulties encountered in the diagnosis of invasive fungal disease, it would be desirable to eliminate the fungal material from antibiotic agents.
Monique A.S.H. Mennink-Kersten, Ph.D.
Adilia Warris, M.D.
Paul E. Verweij, M.D.
Radboud University Nijmegen Medical Center
6500 HB Nijmegen, the Netherlands
m.mennink@mmb.umcn.nl
References
Obayashi T, Yoshida M, Mori T, et al. Plasma (13)-beta-D-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet 1995;345:17-20.
Ostrosky-Zeichner L, Alexander BD, Kett DH, et al. Multicenter clinical evaluation of the (13) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 2005;41:654-659.
Odabasi Z, Mattiuzzi G, Estey E, et al. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 2004;39:199-205.
Mennink-Kersten MASH, Donnelly JP, Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis. Lancet Infect Dis 2004;4:349-357.
Sulahian A, Touratier S, Ribaud P. False positive test for aspergillus antigenemia related to concomitant administration of piperacillin and tazobactam. N Engl J Med 2003;349:2366-2367.