Yoshikiyo Ito

Genetic evolution and clinical impact in extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae

The emergence of extended-spectrum β-lactamase (ESBL)-producing bacteria, particularly Escherichia coli and Klebsiella pneumoniae, is now a critical concern for the development of therapies against bacterial infection. ESBLs consist of three major genetic groups: TEM, SHV, and CTX-M types. Nosocomial infections due to TEM and SHV-producing K. pneumoniae strains were frequently documented until the late 1990s. The number of reports on community-acquired infections caused by CTX-M-producing E. coli strains have dramatically increased over the last decade; however, K. pneumoniae strains, of either the TEM or SHV types, are persistent and important ESBL producers. The spread of ESBL genes is associated with various mobile genetic elements, such as transposons, insertion sequences, and integrons. The rapid dissemination of ESBL genes of the CTX-M type may be related to highly complicated genetic structures. These structures harboring ESBL genes and mobile elements are found in a variety of plasmids, which often carry many other antibiotic resistance genes. Multidrug-resistant CTX-M-15-producing E. coli strains disseminate worldwide. Efficient mobile elements and plasmids may have accelerated the genetic diversity and the rapid spread of ESBL genes, and their genetic evolution has caused an emerging threat to the bacteria for which few effective drugs have been identified.

Clinical impact of fluoroquinolone prophylaxis in neutropenic patients with hematological malignancies

BACKGROUND The routine use of fluoroquinolone prophylaxis in patients with neutropenia and hematological malignancies is controversial. This prophylaxis has been reported to have a positive impact in reducing infection-related mortality, but the consequent development of antibiotic resistance has become a concern. This study assessed the effect of discontinuing quinolone prophylaxis on the etiology and the resistance pattern of blood culture isolates and on the prognosis among febrile neutropenic patients receiving chemotherapy. METHODS The results of blood cultures obtained from febrile neutropenic patients between January 2003 and June 2009 were analyzed; these results were available through a computer database set up in 2003. RESULTS Patients receiving quinolone prophylaxis between 2003 and 2005 showed a lower incidence of Gram-negative bacteria than patients not receiving prophylaxis between 2006 and 2009 (13.5%, n=9 vs. 48.1%, n=75). Interestingly, after discontinuing prophylaxis, approximately 70% of the Gram-negative bacteria isolated were quinolone-resistant, and some were extended-spectrum β-lactamase (ESBL) producers. The frequencies of quinolone-resistant Gram-positive bacteria isolated were similar between the period of quinolone prophylaxis and the period with no prophylaxis (61.1% vs. 64.3%). In both periods, all Gram-positive isolates were sensitive to vancomycin. The infection-related mortality was comparable between patients receiving prophylaxis and those not receiving prophylaxis (1.5%, n=1 vs. 1.3%, n=2). CONCLUSIONS These findings suggest that quinolone prophylaxis for neutropenia does not induce a significant increase in the growth of quinolone- and multidrug-resistant bacteria. Rather, discontinuing quinolone prophylaxis may induce a dramatic increase in the growth of Gram-negative bacteria, including ESBL producers. Our results suggest that the necessity for quinolone prophylaxis in neutropenic patients should be determined based on local antibiotic resistance patterns.

Community spread of extended-spectrum β-lactamase-producing Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis: a long-term study in Japan

Community-acquired infections caused by extended-spectrum β-lactamase (ESBL)-producing bacteria, particularly CTX-M-producing Escherichia coli, are a rising concern worldwide. There are few data from Japan on the acquisition of ESBLs in the community or the influx of these bacteria into hospitals. Therefore, we examined the prevalence of ESBL carriage in outpatients, in order to estimate the spread of ESBLs in community settings. We analysed bacterial isolates from outpatient samples at our institution over a 9-year period from 2003 to 2011, with respect to epidemiological data on ESBL-producing bacteria and their genotypic features. Out of 5137 isolates, 321 (6.3 %) were ESBL producers, including E. coli, Klebsiella pneumoniae and Proteus mirabilis. The detection rates of the ESBL-producing isolates gradually increased and reached 14.3, 8.7 and 19.6 % for E. coli, K. pneumoniae and P. mirabilis strains, respectively, in 2011. Genotyping analysis showed that many of the strains produced multiple β-lactamases, including TEM, SHV and CTX-M, rather than just CTX-M. The CTX-M-9 group was dominant among the CTX-M genotypes; further, the CTX-M-1 and M-2 groups were also detected (~30 %). This is believed to be the first report from Japan showing a definite increase in ESBL detection in outpatients. In addition, our findings suggest the simultaneous community spread of diverse ESBL genotypes, not an expansion of particular ESBL genes.

Cefepime-resistant Gram-negative bacteremia in febrile neutropenic patients with hematological malignancies.

OBJECTIVES This study was performed to determine the local etiologic pattern of blood culture isolates and antibiotic resistance in febrile neutropenic patients with hematological malignancies. METHODS A total of 142 blood culture isolates from febrile neutropenic patients admitted to our hematology unit were examined, particularly for the detection of cefepime resistance, because cefepime, a fourth-generation cephalosporin, has been used in our unit as initial therapy for febrile neutropenia. RESULTS Among all isolates, 67 (47.2%) were Gram-positive bacteria, the majority of which were fully sensitive to vancomycin. Gram-negative bacteria accounted for 68 (47.9%) of the isolates. Cefepime resistance was seen in 24 (35.3%) of the Gram-negative isolates, and had significantly increased in 2007. The cefepime-resistant isolates primarily consisted of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Approximately 60% of the cefepime-resistant isolates were extended-spectrum β-lactamase (ESBL)-producing organisms. Molecular analysis showed the predominant emergence of CTX-M types. Most of the cefepime-resistant isolates were resistant to third- and various fourth-generation cephalosporins, while having a high susceptibility to carbapenems, particularly meropenem. CONCLUSIONS Cefepime resistance was often detected in the blood culture isolates from febrile neutropenic patients. This result suggests that therapeutic strategies for febrile neutropenia should be modified based on the local antibiotic resistance patterns.

Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen

Subcutaneous (sc) rather than intravenous administration of bortezomib (Bor) is becoming more common for treating multiple myeloma (MM) because scBor results in lower incidence and severity of peripheral neuropathy and has equivalent efficacy. Bor is an irritant cytotoxic agent when it leaks out; therefore, it is recommended that injections of scBor should be rotated among eight different sites on the abdomen and thigh. However, detailed information about injection site reaction (ISR) has not been sufficiently documented. We retrospectively analyzed the incidence and severity of ISR following scBor administration in 15 Japanese patients with MM. Grade 1 ISR occurred following 40 of 158 (25.3%) scBor injections in ten patients, whereas grade 2 ISRs occurred following seven injections (4.4%) in five patients. Five patients did not develop ISR. Of note, grade 2 ISR was documented in 6 of 65 (9.2%) thigh injections but only in 1 of 93 (1.1%) abdominal injections. These data show that grade 2 ISRs were more common in the thigh compared with the abdomen possibly because the thigh contains lesser adipose tissue than the abdomen. Grade 2 ISRs resolved without any sequela within a median of 7 d. scBor administration on the abdomen instead of the thigh should be considered, especially for emaciated patients, because ISR rapidly resolves within the interval before the next injection even if it occurs.

Successful treatment with anti-CC chemokine receptor 4 MoAb of relapsed adult T-cell leukemia/lymphoma after umbilical cord blood transplantation.

Successful treatment with anti-CC chemokine receptor 4 MoAb of relapsed adult T-cell leukemia/lymphoma after umbilical cord blood transplantation

Antibiotic Rotation for Febrile Neutropenic Patients with Hematological Malignancies: Clinical Significance of Antibiotic Heterogeneity

Background Our unit adopted the single administration of cefepime as the initial treatment for febrile episodes in neutropenic patients with hematological malignancies. However, recently, cefepime-resistant gram-negative bacteremia, including those with extended-spectrum β-lactamase (ESBL)-producers, was frequently observed in these patients. Therefore, we instituted a rotation of primary antibiotics for febrile neutropenic patients in an attempt to control antibiotic resistance. Methods This prospective trial was performed from August 2008 through March 2011 at our unit. After a pre-intervention period, in which cefepime was used as the initial agent for febrile neutropenia, 4 primary antibiotics, namely, piperacillin-tazobactam, ciprofloxacin, meropenem, and cefepime, were rotated at 1-month intervals over 20 months. Blood and surveillance cultures were conducted for febrile episodes, in order to assess the etiology, the resistance pattern (particularly to cefepime), and the prognosis. Results In this trial, 219 patients were registered. A 65.9% reduction in the use of cefepime occurred after the antibiotic rotation. In the surveillance stool cultures, the detection rate of cefepime-resistant gram-negative isolates, of which ESBL-producers were predominant, declined significantly after the intervention (8.5 vs 0.9 episodes per 1000 patient days before and after intervention respectively, P<0.01). Interestingly, ESBL-related bacteremia was not detected after the initiation of the trial (1.7 vs 0.0 episodes per 1000 patient days before and after intervention respectively, P<0.01). Infection-related mortality was comparable between the 2 periods. Conclusions We implemented a monthly rotation of primary antibiotics for febrile neutropenic patients. An antibiotic heterogeneity strategy, mainly performed as a cycling regimen, would be useful for controlling antimicrobial resistance among patients treated for febrile neutropenia.

Clinical impact of fluoroquinolone-resistant Escherichia coli in the fecal flora of hematological patients with neutropenia and levofloxacin prophylaxis

Background Fluoroquinolone prophylaxis in patients with neutropenia and hematological malignancies is said to be effective on febrile netropenia (FN)-related infection and mortality; however, the emergence of antibiotic resistance has become a concern. Ciprofloxacin and levofloxacin prophylaxis are most commonly recommended. A significant increase in the rate of quinolone-resistant Escherichia coli in fecal flora has been reported following ciprofloxacin prophylaxis. The acquisition of quinolone-resistant E. coli after levofloxacin use has not been evaluated. Methods We prospectively examined the incidence of quinolone-resistant E. coli isolates recovered from stool cultures before and after levofloxacin prophylaxis in patients with neutropenia from August 2011 to May 2013. Some patients received chemotherapy multiple times. Results In this trial, 68 patients were registered. Levofloxacin-resistant E. coli isolates were detected from 11 and 13 of all patients before and after the prophylaxis, respectively. However, this was not statistically significant (P = 0.65). Multiple prophylaxis for sequential chemotherapy did not induce additional quinolone resistance among E. coli isolates. Interestingly, quinolone-resistant E. coli, most of which were extended-spectrum β-lactamase (ESBL) producers, were already detected in approximately 20% of all patients before the initiation of prophylaxis. FN-related bacteremia developed in 2 patients, accompanied by a good prognosis. Conclusions Levofloxacin prophylaxis for neutropenia did not result in a significant acquisition of quinolone-resistant E. coli. However, we detected previous colonization of quinolone-resistant E. coli before prophylaxis, which possibly reflects the spread of ESBL. The epidemic spread of resistant E. coli as a local factor may influence strategies toward the use of quinolone prophylaxis.

Role of autotransplantation in the treatment of acute promyelocytic leukemia patients in remission: Fukuoka BMT Group observations and a literature review

We retrospectively analyzed the outcomes of 26 patients with acute promyelocytic leukemia (APL) in the first CR (CR1) or second CR (CR2), who underwent autologous PBSCT (auto-PBSCT) between 1992 and 2008. All patients received all-trans retinoic acid-based induction therapy. After two courses of consolidation chemotherapy, upfront auto-PBSCT was performed in 20 patients in the CR1. Five patients had a high WBC count of more than 10 × 109/L (high risk), while 15 patients had a count of less than 10 × 109/L (low risk) at initial presentation. In addition, six patients, who were considered as low-risk patients at presentation, had a relapse after three cycles of consolidation and 2 years of maintenance therapy, but gained the molecular remission after re-induction and consolidation, and underwent auto-PBSCT in the CR2. In 26 recipients, engraftment was rapid and no TRM was documented. All 20 patients autotransplanted in CR1 were still in CR at a median of 133 months (73–193 months), and six patients who underwent auto-PBSCT in CR2 were also still in CR at a median of 41 months (2–187 months) without maintenance therapy. PML/RARα chimeric mRNA was undetectable in PBSC or BM samples examined before auto-PBSCT. Despite a small number of cases studied, our retrospective observations suggest that auto-PBSCT may be an effective treatment option to continue durable CR in the treatment of high-risk APL. We review previous reports and discuss the role of autotransplantation in the treatment of APL patients in CR.

Therapy-related chronic myelogenous leukaemia following autologous stem cell transplantation for Ewing's sarcoma

Summary. A 17‐year‐old Japanese woman with Ewings sarcoma was initially treated with conventional chemotherapy and local irradiation, and then with high‐dose chemotherapy supported by autologous peripheral blood stem cell transplantation. Four years later she was diagnosed with chronic myelogenous leukaemia (CML). The BCR/ABL fusion gene was detected in both peripheral blood and bone marrow cells by reverse transcription–polymerase chain reaction, but not in the harvest product of peripheral blood stem cells which were infused at the time of transplantation. This case adds to the accumulating evidence of therapy‐related CML developing after high‐dose chemotherapy and autologous stem cell transplantation.