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 ß-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.

The mechanism of high-level carbapenem resistance in Klebsiella pneumoniae: underlying Ompk36-deficient strains represent a threat of emerging high-level carbapenem-resistant K. pneumoniae with IMP-1 ß-lactamase production in Japan.

The mechanisms of high-level carbapenem resistance in Klebsiella pneumoniae isolated in Japan were investigated. High-level carbapenem-resistant K. pneumoniae Mkp4437 and a less carbapenem-sensitive K. pneumoniae strain, Mkp4365, were recovered from the same patient. These two strains were found to be homologous by pulsed-field gel electrophoresis, and both strains contained blaIMP-1, blaDHA-1, blaCTXM-14, blaTEM-1, and blaSHV-1. Based on the sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, the lack of Ompk36 was observed in Mkp4437. Direct sequencing of the ompK36 gene demonstrated that a new insertional sequence in the open reading frame of the ompK36 gene was found in Mkp4437. Three clinical isolates (minimum inhibitory concentration [MIC] 2-4 mg/L to imipenem) were identified upon screening the strains of K. pneumoniae isolated in the University hospital with MICs of ≥ 1 mg/L to imipenem. Interestingly, these three isolates all lacked OmpK36. Conjugation of the plasmid harboring IMP-1 to these three OmpK36-deficient strains led to the isolation of high-level carbapenem-resistant transconjugants. In conclusion, the mechanisms of high-level carbapenem resistance in K. pneumoniae entail not only the production of IMP-1 ß-lactamase but also the lack of OmpK36. It is vital to monitor for the presence of less carbapenem-sensitive K. pneumoniae strains, which lack OmpK36, because blaIMP-1 transmission to these strains may result in isolates with a high-level carbapenem-resistant phenotype.

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

Community-acquired infections caused by extended-spectrum ß-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 ß-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.

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 ß-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.

Fatal candidemia caused by azole-resistant Candida tropicalis in patients with hematological malignancies.

Candida tropicalis is one of the most important Candida species causative of candidemia that is isolated from the blood of patients with hematological malignancies. Candidemia caused by C. tropicalis is known to be highly virulent in neutropenic patients. C. tropicalis has been shown to be favorably sensitive to azole agents in general. Here we discuss 5 cases of candidemia caused by C. tropicalis in patients with hematological malignancies in our unit, and we note that 4 isolates were resistant to azole agents, including fluconazole, itraconazole, and voriconazole. In addition, 2 patients developed breakthrough candidemia caused by C. tropicalis while receiving prophylaxis with azole agents. Interestingly, 2 of the 4 patients with azole-resistant C. tropicalis isolates had never received any antifungal drugs. We also examined the susceptibilities of C. tropicalis to antifungal agents, using 39 non-blood isolates detected from 2003 to 2009. Around 40 % of the isolates were resistant to azole agents, and all of them were highly sensitive to amphotericin B and micafungin. The resistance to azoles was not associated with previous exposure to those agents. In our unit, 2 of the 4 cases of candidemia caused by azole-resistant C. tropicalis resulted in a poor prognosis. These findings suggested that empirical therapeutic strategies for candidemia should be modified based on the local antifungal resistance pattern.

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 ß-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.

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 ß-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.