piperacillin--tazobactam-drug-combination and galactomannan

Galactomannan (GM) assay is commonly used as an early diagnostic tool for invasive fungal infection (IFI) in high-risk hematology patients. False positivity is frequently observed in GM with the use of piperacillin/tazobactam. The usage of generic drugs over the original brand has a significant cost advantage. The aim of this study was to assess the performance of GM test among patients receiving original and generic piperacillin/tazobactam formulations. The study included 85 adult patients; 62.4% were male with hematological malignancy currently receiving piperacillin/tazobactam. The study group was divided into two groups: patients receiving original and generic piperacillin/tazobactam. Serum GM index was positive in one of 35 patients receiving original piperacillin/tazobactam, whereas it was positive in 46 out of 50 patients receiving generic piperacillin/tazobactam (P < .001). However, the patients receiving generic piperacillin/tazobactam underwent computed tomography (CT) scans more frequently than those receiving original piperacillin/tazobactam (P = .047). In addition, in vitro analysis of GM was performed in two generics and one original piperacillin/tazobactam vials. One generic piperacillin/tazobactam vial included high GM level. False positivity of serum GM with generic formulations of piperacillin/tazobactam is still an ongoing issue in hematology patients. A high rate of serum GM index false positivity may unexpectedly lead to a higher rate of CT scan. Selected piperacillin/tazobactam vials in each batch should be checked for GM to identify a false positivity of GM before purchase.

Topics: Anti-Bacterial Agents; Antigens, Fungal; False Positive Reactions; Febrile Neutropenia; Female; Galactose; Humans; Invasive Pulmonary Aspergillosis; Male; Mannans; Microbiological Techniques; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

Piperacillin-tazobactam (PTZ) is known to cause false-positive results in the Platelia Aspergillus enzyme-linked immunoassay (EIA), due to contamination with galactomannan (GM). We tested 32 lots of PTZ and 27 serum specimens from patients receiving PTZ. GM was not detected in the lots of PTZ; one serum specimen (3.7%) was positive. PTZ formulations commonly used in the United States today appear to be a rare cause for false-positive GM results.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Aspergillosis; Aspergillus; Diagnostic Tests, Routine; Drug Contamination; False Positive Reactions; Female; Galactose; Humans; Immunoenzyme Techniques; Mannans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Serum; United States

Invasive aspergillosis is a serious disease, the lethality of which is important among hematology patients. Early diagnosis is crucial for treatment options and the prognosis. Detection of the antigen galactomannan is the most frequently used microbiological tools. But galactomannan detection may be falsely positive, and this false positivity has been associated with piperacillin-tazobactam treatment, the main antibiotic combination used in clinical hematology.. The purpose of our study, carried out from January 2009 to December 2010 at the Versailles hospital on in-patients with hematological disorders, was to evaluate the association between false galactomannan positivity and administration of piperacillin-tazobactam, and to study a possible variability of products issued by three manufacturers.. We noted that 207 patients were included (n=207), accounting for 69 false positive and 138 true negative results. The intrinsic galactomannan values in the study were sensitivity 100%, specificity 68%, positive and negative predictive values respectively 16%, 100%, and a likelihood positive and negative test at respectively 3.12, and 0.. The statistical analysis did not determine any association between false positivity in galactomannan and piperacillin-tazobactam issued by two manufacturers (P=0.87 and P=0.94). But, there was a significant association between false galactomannan positivity and piperacillin-tazobactam issued by the third manufacturer (P=0.02). Four of the 25 batches issued by this manufacturer were tested and negative "in vitro" for galactomannan.. This study results suggest that the association between false galactomannan positivity and piperacillin-tazobactam is not longer systematic, but can still prevail depending on the manufacturers. It also confirmed the positive contribution of testing piperacillin-tazobactam batches "in vitro" before using the antibiotic.

Topics: Anti-Bacterial Agents; Antigens, Fungal; Artifacts; Aspergillosis; Biomarkers; Enzyme-Linked Immunosorbent Assay; False Positive Reactions; Fungemia; Galactose; Humans; Mannans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Reagent Kits, Diagnostic; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity

Galactomannan (GM) testing is extremely useful for diagnosing invasive aspergillosis in high-risk patients, but false-positive results have been reported in patients treated with piperacillin/tazobactam. The aims of this study are to test if the recent piperacillin/tazobactam (Tazocin™; Pfizer) preparation still contains GM, and if serum GM positivity in haematopoietic stem cell transplant (HSCT) recipients receiving piperacillin/tazobactam can be attributed to this treatment.. Serum samples obtained from 1 October 2009 to 31 October 2010 from HSCT recipients for GM testing were analysed. The difference in the rate of positive results (defined as GM ≥ 0.5) in patients receiving and not receiving piperacillin/tazobactam was evaluated. Piperacillin/tazobactam vials from randomly selected batches were tested.. Of 1606 samples drawn in the absence of piperacillin/tazobactam therapy, 25 (1.6%) tested positive for GM versus 10 of 394 samples (2.5%) drawn while on piperacillin/tazobactam (P = 0.18). The median GM result of samples drawn on piperacillin/tazobactam was slightly higher than that of samples drawn in the absence of piperacillin/tazobactam (0.141 versus 0.122; P < 0.001). All 90 piperacillin/tazobactam vials from 30 randomly selected batches tested negative for GM, with a median GM value of 0.057 (range: 0.011-0.320).. Although some residual GM might still be present in piperacillin/tazobactam, currently available brand piperacillin/tazobactam preparations seem no longer responsible for false-positive GM results.

Topics: Anti-Bacterial Agents; Aspergillosis; False Positive Reactions; Galactose; Hematopoietic Stem Cell Transplantation; Humans; Mannans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

The aim of this study was to investigate the interaction between intravenous piperacillin/tazobactam treatment and Aspergillus galactomannan antigen (GM) and 1,3-beta-D: -glucan (BDG) test results in patients without known risk factors for invasive fungal infections (IFI).. Patients without known risk factors for IFI and who were to receive piperacillin/tazobactam monotherapy were considered eligible for the study. Serum samples were obtained both before and after antibiotic infusion on the first, third, seventh and tenth days of a piperacillin/tazobactam treatment course and 4 days after the last dose. GM was determined by Platelia Aspergillus ELISA (Bio-Rad Laboratories) and BDG was assayed using the Fungitell kit (Associates of Cape Cod, East Falmouth, MA) according to manufacturers' specifications.. A total of 135 serum samples were collected from 15 patients. When a cut-off level of >or=0.7 was used for GM positivity, there were no false positive results. When a cut-off level of >or=0.5 was used, six serum samples were positive. There were no statistically significant differences between the median GM indices or median BDG levels of the various sampling times. However, 24 of 135 serum samples were positive for BDG for a threshold of 80 pg/mL. After ruling out fungal infections and all known potential causes of false BDG positivity, environmental contamination remained a possible cause of BDG reactivity.. No significant interaction was observed between piperacillin/tazobactam administration and Aspergillus GM and BDG assays. Positive results for these tests should be evaluated cautiously in patients at high risk for IFI receiving piperacillin/tazobactam.

Topics: Adult; Aged; Anti-Bacterial Agents; Antigens, Fungal; Aspergillosis; Aspergillus; beta-Glucans; False Positive Reactions; Female; Galactose; Humans; Infusions, Intravenous; Male; Mannans; Microbiological Techniques; Middle Aged; Mycology; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Risk Factors

Invasive aspergillosis (IA) remains one of the most significant causes of morbidity and mortality in patients with hematological malignancies undergoing chemotherapy and hematopoietic stem cell transplantation (HSCT), mainly due to the difficulty in its early diagnosis. Monitoring of galactomannan (GM) antigen, an exoantigen of Aspergillus, in the blood by sandwich ELISA is a useful and noninvasive method for early diagnosis of IA. The GM test has a sensitivity of 67-100% with a specificity of 81-99% in neutropenic patients and allogeneic transplant recipients [1-3]. Although it has been widely used as a diagnostic criterion for IA [4,5], one of the major limitations of this assay is false-positivity, particularly in pediatric patients [1], patients with graft-versus-host disease (GVHD) [6,7], and those taking dietary GM [8,9] or fungus-derived antibiotics, such as piperacillin-tazobactam (PIPC/TAZ) [10-12].

Topics: Amoxicillin; Antibiotic Prophylaxis; Antigens, Fungal; Artifacts; Aspergillosis; Aspergillus; False Positive Reactions; Galactose; Hematologic Diseases; Hematologic Neoplasms; Humans; Immunoglobulin G; Mannans; Multiple Myeloma; Myeloma Proteins; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Sensitivity and Specificity

Piperacillin-tazobactam is a broad spectrum antimicrobial agent that can cause false-positive results in the commercial Platelia Aspergillus EIA test. So far, no study has been performed in Latin America to evaluate the clinical implication of this finding. Here we studied the potential for galactomannan detection in piperacillin-tazobactam batches commercialized in the Brazilian market. Five batches from distinct laboratories were tested in duplicate in the Platelia Aspergillus EIA according to the manufacturer's instructions. Only one drug showed crossreaction at a cut-off of 0.5. Human serum was spiked with this particular drug aiming to mimic achievable piperacillin-tazobactam concentrations in the serum. Results were all negative for galactomannan detection, even at high drug concentrations. Results from this pilot study suggest that piperacillin-tazobactam might not be a clinically significant cause of false-positive results in the Platelia Aspergillus EIA test in Brazil.

Topics: Anti-Bacterial Agents; Aspergillus; False Positive Reactions; Galactose; Immunoenzyme Techniques; Mannans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

In this prospective study including 78 adult patients with haematological malignancy (90 episodes) we performed galactomannan (GM) (Platelia Aspergillus) screening twice weekly for the diagnosis of invasive aspergillosis. There were five proven and four probable invasive aspergillosis cases. The sensitivity, specificity and positive and negative predictive values were 100, 88, 47 and 100%, respectively. There were eight patients with false positive GM (10.2%). In six patients the false GM reactivity was due to the administration of piperacillin-tazobactam (P-T). A significant association was found between false positive GM (= or > 0.5) and the administration of P-T (p < 0.01). Two other patients with no invasive aspergillosis (2.5%) and false GM reactivity had graft versus host disease (GVHD) and one of them had also mucositis grade IV. The kinetic patterns of false positive GM due to P-T is discussed.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Artifacts; Aspergillosis; Biomarkers; Combined Modality Therapy; Enzyme-Linked Immunosorbent Assay; False Positive Reactions; Female; Fungemia; Galactose; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Mannans; Middle Aged; Mucositis; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Predictive Value of Tests; Prospective Studies; Sensitivity and Specificity

The diagnosis of invasive aspergillosis which is a serious infection of immunocompromized patients, depends on the detection of Aspergillus galactomannan antigen in the serum by enzyme immunoassay (EIA) in routine laboratories. However, it has been previously reported that false positive results in Aspergillus galactomannan test may be obtained in the sera of patients sera receiving piperacillin-tazobactam (PIP-TAZ). The aim of this study was to investigate the presence and levels of Aspergillus galactomannan antigen in the content of PIP-TAZ and some other antimicrobial agents that are often used for the treatment of infections in immunocompromised patients. The level of galactomannan antigen was determined for PIP-TAZ, ampicillin-sulbactam, ampicillin, penicillin G, ceftriaxone, cefepime, imipenem, clarithromycin, ciprofloxacin, vancomycin, gentamicin, trimethoprim-sulfamethoxazole, ornidazole, fluconazole and amphotericin B, by a commercial EIA (Platelia Aspergillus EIA, Bio-Rad, France) kit. Galactomannan index (GI) was estimated with the ratio of absorbance values of antimicrobials to cut-off value and evaluated as positive when GI was found >0.5. Amongst the 15 antibiotics studied, the only positive result was detected for ampicillin with the highest index value (GI = 0.540), followed by PIP-TAZ with a relatively high value (GI = 0.235) even though it was not in the range of positivity. GI values have ranged from 0.011 to 0.188 for the other antibiotics. In conclusion, the use of especially ampicillin (and probably PIP-TAZ) therapy should be questioned in patients whose sera are being tested for Aspergillus galactomannan antigen by EIA in order to evaluate the positive results in terms of false positivities due to cross reactivity.

Topics: Ampicillin; Anti-Bacterial Agents; Antigens, Fungal; Aspergillosis; Aspergillus; Cross Reactions; Drug Contamination; False Positive Reactions; Galactose; Humans; Immunoenzyme Techniques; Mannans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

The association between piperacillin/tazobactam and the positivity of the galactomannan (GM) detection ELISA test is well described. Little information is available about the kinetics of GM in patients treated with piperacillin/tazobactam. The present study aimed at clarifying the baseline interaction between piperacillin/tazobactam and GM in patients receiving this drug.. Seven patients undergoing abdominal surgery received perioperative prophylaxis with piperacillin/tazobactam. Each patient received three doses of 4.5 g of the drug, administered at 8 h intervals (one before and two after surgery). Three patients received antibiotic batches with 'medium' (GM-index = 1.782) and four patients received antibiotic batches with 'high' (GM-index = 6.665) GM content. Serum samples for GM evaluation were collected before drug infusion and at times +1, +3, +6 and +8 h after the first and third infusions.. GM levels increased after infusion, in particular when batches with 'high' GM content were used. Moreover, a non-statistically significant increase between the first dose and the third dose was observed. All samples taken >6 h after administration were negative (GM-index < 0.2), both with the 'medium' and the 'high' GM content batches.. The low content of GM 8 h after piperacillin/tazobactam infusion suggests that in non-neutropenic cancer patients with solid tumours receiving up to three doses of piperacillin/tazobactam, serum sampling for GM detection should be performed immediately before the next piperacillin/tazobactam administration.

Topics: Aged; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacterial Infections; Colon; False Positive Reactions; Female; Galactose; Gastrectomy; Humans; Kinetics; Male; Mannans; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Rectum

Topics: Anti-Bacterial Agents; Aspergillosis; Drug Contamination; Galactose; Humans; Mannans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

At the bone marrow transplantation center of the San Martino Hospital (Genoa), we observed an increase in the rate of patients with positive Platelia Aspergillus (PA; Bio-Rad) test results, from 10% (38 of 386 patients) in the period from January 1999 through January 2003 to 36% (21 of 59 patients) in the period from February 2003 through May 2003. Positivity was significantly (P<.001) associated with the administration of piperacillin-tazobactam (PT) (17 [74%] of 23 patients who received PT had positive results vs. 4 [11%] of 36 who did not receive PT). Multivariate analysis found administration of PT ( chi 2=34.7; P<.001) and underlying disease ( chi 2=21.14; P<.001) to be associated with PA positivity. Of 15 PT batches tested, 12 had positive PA test results.

Topics: Anti-Bacterial Agents; Antigens, Fungal; Aspergillus; False Positive Reactions; Galactose; Humans; Mannans; Microbiological Techniques; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Sensitivity and Specificity

We report the occurrence of a high rate of false-positive test results during the surveillance of hematology patients for galactomannan (GM) antigenemia. Among 218 patients surveyed from June 2002 through June 2003, 42 (19.3%) had > or =1 serum sample positive for GM (optical density index, >1.5). Of these patients, 38 had no additional evidence of invasive aspergillosis, and, therefore, their test results were considered to be false-positives. Case-control analysis showed that treatment with piperacillin-tazobactam was the only risk factor significantly associated with receiving false-positive test results. When tested for GM antigen, 3 of 4 piperacillin-tazobactam batches had positive results. Physicians should be aware of the possible interference of treatment with piperacillin-tazobactam when interpreting the results of the GM assay.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antigens, Fungal; Aspergillus; Case-Control Studies; False Positive Reactions; Female; Galactose; Hematologic Neoplasms; Humans; Male; Mannans; Microbiological Techniques; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Sensitivity and Specificity

Topics: Adult; Amoxicillin-Potassium Clavulanate Combination; Antigens, Fungal; Aspergillus; False Positive Reactions; Galactose; Humans; Male; Mannans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

Recent case reports describe patients receiving piperacillin-tazobactam who were found to have circulating galactomannan detected by the double sandwich enzyme-linked immunosorbent assay (ELISA) system, leading to the false presumption of invasive aspergillosis. Since this property of piperacillin-tazobactam and galactomannan ELISA is not well understood, we investigated the in vitro, in vivo, and clinical properties of this interaction. Among the 12 reconstituted antibiotics representing four classes of antibacterial compounds that are commonly used in immunocompromised patients, piperacillin-tazobactam expressed a distinctively high level of galactomannan antigen in vitro (P = 0.001). After intravenous infusion of piperacillin-tazobactam into rabbits, the serum galactomannan index (GMI) in vivo changed significantly (P = 0.0007) from a preinfusion mean baseline value of 0.27 to a mean GMI of 0.83 by 30 min to slowly decline to a mean GMI of 0.44 24 h later. Repeated administration of piperacillin-tazobactam over 7 days resulted in accumulation of circulating galactomannan to a mean peak GMI of 1.31 and a nadir of 0.53. Further studies revealed that the antigen reached a steady state by the third day of administration of piperacillin-tazobactam. Twenty-six hospitalized patients with no evidence of invasive aspergillosis who were receiving antibiotics and ten healthy blood bank donors were studied for expression of circulating galactomannan. Patients (n = 13) receiving piperacillin-tazobactam had significantly greater mean serum GMI values (0.74 +/- 0.14) compared to patients (n = 13) receiving other antibiotics (0.14 +/- 0.08) and compared to healthy blood bank donors (0.14 +/- 0.06) (P < 0.001). Five (38.5%) of thirteen patients receiving piperacillin-tazobactam had serum GMI values > 0.5 compared to none of thirteen subjects receiving other antibiotics (P = 0.039) and to none of ten healthy blood bank donors (P = 0.046). These data demonstrate that among antibiotics that are commonly used in immunocompromised patients, only piperacillin-tazobactam contains significant amounts of galactomannan antigen in vitro, that in animals receiving piperacillin-tazobactam circulating galactomannan antigen accumulates in vivo to significantly increased and sustained levels, and that some but not all patients receiving this antibiotic will demonstrate circulating galactomannan above the threshold considered positive for invasive aspergillosis by the recently licensed

Topics: Animals; Anti-Bacterial Agents; Antigens, Fungal; Aspergillosis; Enzyme-Linked Immunosorbent Assay; False Positive Reactions; Female; Galactose; Humans; Mannans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Rabbits

Topics: Adult; Aged; Aspergillus; False Positive Reactions; Galactose; Humans; Mannans; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Reagent Kits, Diagnostic