BACKGROUND: Acinetobacter baumannii has emerged as a major cause of nosocomial outbreaks. It is particularly associated with nosocomial pneumonia and bloodstream infections in immunocompromised and debilitated patients with serious underlying pathologies. Over the last two decades, a remarkable rise in the rates of multidrug resistance to most antimicrobial agents that are active against A. baumannii has been noted worldwide. We evaluated the rates of antimicrobial resistance and changes in resistance over a 5-year period (2010–2014) in A. baumannii strains isolated from hospitalized patients in a tertiary Greek hospital. MATERIALS AND METHODS: Identification of A. baumannii was performed by standard biochemical methods and the Vitek 2 automated system, which was also used for susceptibility testing against 18 antibiotics: ampicillin/sulbactam, ticarcillin, ticarcillin/clavulanic acid, piperacillin, piperacillin/tazobactam, cefotaxime, ceftazidime, cefepime, imipenem, meropenem, gentamicin, amikacin, tobramycin, ciprofloxacin, tetracycline, tigecycline, trimethoprim/sulfamethoxazole, and colistin. Interpretation of susceptibility results was based on the Clinical and Laboratory Standards Institute criteria, except for tigecycline, for which the Food and Drug Administration breakpoints were applied. Multidrug resistance was defined as resistance to ≥3 classes of antimicrobial agents. RESULTS: Overall 914 clinical isolates of A. baumannii were recovered from the intensive care unit (ICU) (n = 493), and medical (n = 252) and surgical (n = 169) wards. Only 4.9% of these isolates were fully susceptible to the antimicrobials tested, while 92.89% of them were multidrug resistant (MDR), i.e., resistant to ≥3 classes of antibiotics. ICU isolates were the most resistant followed by isolates from surgical and medical wards. The most effective antimicrobial agents were, in descending order: colistin, amikacin, trimethoprim/sulfamethoxazole, tigecycline, and tobramycin. Nevertheless, with the exception of colistin, no antibiotic was associated with a susceptibility rate >40% for the entire study period. The most common phenotype showed resistance against ampicillin/sulbactam, cephalosporins, carbapenems, aminoglycosides, ciprofloxacin, and tigecycline. An extremely concerning increase in colistin-resistant isolates (7.9%) was noted in 2014, the most recent study year. CONCLUSION: The vast majority of A. baumannii clinical isolates in our hospital are MDR. The remaining therapeutic options for critically ill patients who suffer from MDR A. baumannii infections are severely limited, with A. baumannii beginning to develop resistance even against colistin. Scrupulous application of infection control practices should be implemented in every hospital unit. Lastly, given the lack of available therapeutic options for MDR A. baumannii infections, well-controlled clinical trials of combinations of existing antibiotics are clearly needed.
Acinetobacter baumannii* ; Acinetobacter* ; Amikacin ; Aminoglycosides ; Anti-Bacterial Agents ; Anti-Infective Agents ; Carbapenems ; Cefotaxime ; Ceftazidime ; Cephalosporins ; Ciprofloxacin ; Colistin ; Critical Illness ; Disease Outbreaks ; Drug Resistance, Multiple ; Gentamicins ; Hospital Units ; Humans ; Imipenem ; Infection Control ; Intensive Care Units ; Pathology ; Phenotype ; Piperacillin ; Pneumonia ; Tetracycline ; Ticarcillin ; Tobramycin ; United States Food and Drug Administration

PURPOSE: Transrectal ultrasonography-guided prostate biopsy (TRUS-Bx) is an essential procedure for diagnosing prostate cancer. The American Urological Association (AUA) Guideline recommends fluoroquinolone alone for 1 day during TRUS-Bx. However, this recommendation may not be appropriate in regions where the prevalence of quinolone-resistant Escherichia coli is high. We investigated the real practice of antibiotic prophylaxis for TRUS-Bx in Korea. MATERIALS AND METHODS: A total of 77 hospitals performing TRUS-Bx were identified and an e-mail was sent to the Urology Department of those hospitals. The questions in the e-mail included the choice of antibiotics before and after the procedure and the duration of antibiotic therapy after TRUS-Bx. RESULTS: A total of 54 hospitals (70.0%) responded to the e-mail. Before TRUS-Bx, all hospitals administered intravenous antibiotic prophylaxis. The percentage of hospitals that used quinolone, cephalosporin, and aminoglycoside alone was 48.1%, 20.4%, and 9.3%, respectively. The percentage of hospitals that used two or more antibiotics was 22.2%. After biopsy, all 54 hospitals prescribed oral antibiotics. The percentage of hospitals that prescribed quinolone alone, cephalosporin alone, or a combination of two or more antibiotics was 77.8%, 20.4%, and 1.8%, respectively. The duration of antibiotic use was more than 3 days in most hospitals (79.6%). Only four hospitals (7.4%) followed the AUA recommendation of a 1-day regimen. CONCLUSIONS: The AUA recommendation was not followed by most hospitals in Korea. This clinical behavior might reflect the high quinolone resistance rate in Korea, and further studies on the most efficient prophylactic antibiotics after TRUS-Bx in Korea are warranted.
Aminoglycosides/*administration & dosage ; Anti-Bacterial Agents/*administration & dosage ; Antibiotic Prophylaxis/*methods ; Biopsy/adverse effects ; Cephalosporins/*administration & dosage ; Cross-Sectional Studies ; Drug Resistance, Bacterial ; Escherichia coli Infections/*prevention & control ; Humans ; Male ; Prostate/pathology ; Prostatic Neoplasms/pathology ; Quinolones/*administration & dosage ; Republic of Korea

PURPOSE: Transrectal ultrasonography-guided prostate biopsy (TRUS-Bx) is an essential procedure for diagnosing prostate cancer. The American Urological Association (AUA) Guideline recommends fluoroquinolone alone for 1 day during TRUS-Bx. However, this recommendation may not be appropriate in regions where the prevalence of quinolone-resistant Escherichia coli is high. We investigated the real practice of antibiotic prophylaxis for TRUS-Bx in Korea. MATERIALS AND METHODS: A total of 77 hospitals performing TRUS-Bx were identified and an e-mail was sent to the Urology Department of those hospitals. The questions in the e-mail included the choice of antibiotics before and after the procedure and the duration of antibiotic therapy after TRUS-Bx. RESULTS: A total of 54 hospitals (70.0%) responded to the e-mail. Before TRUS-Bx, all hospitals administered intravenous antibiotic prophylaxis. The percentage of hospitals that used quinolone, cephalosporin, and aminoglycoside alone was 48.1%, 20.4%, and 9.3%, respectively. The percentage of hospitals that used two or more antibiotics was 22.2%. After biopsy, all 54 hospitals prescribed oral antibiotics. The percentage of hospitals that prescribed quinolone alone, cephalosporin alone, or a combination of two or more antibiotics was 77.8%, 20.4%, and 1.8%, respectively. The duration of antibiotic use was more than 3 days in most hospitals (79.6%). Only four hospitals (7.4%) followed the AUA recommendation of a 1-day regimen. CONCLUSIONS: The AUA recommendation was not followed by most hospitals in Korea. This clinical behavior might reflect the high quinolone resistance rate in Korea, and further studies on the most efficient prophylactic antibiotics after TRUS-Bx in Korea are warranted.
Aminoglycosides/*administration & dosage ; Anti-Bacterial Agents/*administration & dosage ; Antibiotic Prophylaxis/*methods ; Biopsy/adverse effects ; Cephalosporins/*administration & dosage ; Cross-Sectional Studies ; Drug Resistance, Bacterial ; Escherichia coli Infections/*prevention & control ; Humans ; Male ; Prostate/pathology ; Prostatic Neoplasms/pathology ; Quinolones/*administration & dosage ; Republic of Korea

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of myeloid precursors arrested in their maturation, creating a diverse disease entity with a wide range of responses to historically standard treatment approaches. While significant progress has been made in characterizing and individualizing the disease at diagnosis to optimally inform those affected, progress in treatment to reduce relapse and induce remission has been limited thus far. In addition to a brief summary of the factors that shape prognostication at diagnosis, this review attempts to expand on the current therapies under investigation that have shown promise in treating AML, including hypomethylating agents, gemtuzumab ozogamicin, FLT3 tyrosine kinase inhibitors, antisense oligonucleotides, and other novel therapies, including aurora kinases, mTOR and PI3 kinase inhibitors, PIM kinase inhibitors, HDAC inhibitors, and IDH targeted therapies. With these, and undoubtedly many others in the future, it is the hope that by combining more accurate prognostication with more effective therapies, patients will begin to have a different, and more complete, outlook on their disease that allows for safer and more successful treatment strategies.
Aminoglycosides ; administration & dosage ; Antibodies, Monoclonal, Humanized ; administration & dosage ; Elafin ; genetics ; Histone Deacetylase Inhibitors ; therapeutic use ; Humans ; Isocitrate Dehydrogenase ; Leukemia, Myeloid, Acute ; drug therapy ; genetics ; pathology ; Proto-Oncogene Proteins c-pim-1 ; metabolism ; TOR Serine-Threonine Kinases ; genetics

This study is to investigate the inhibitory effect of lidamycin (LDM) and its combination with methotrexate (MTX) on lung metastasis of fibrosarcoma by bioluminescence imaging in athymic mice. A stable luciferase transfected HT-1080 cell line was constructed and the capability to establish experimental lung metastasis in athymic mice was confirmed. The optical imaging system was applied to evaluate the formation of lung metastasis in vivo. In addition, metastatic nodules were counted for the evaluation of inhibition rates. As shown, the fluorescent intensity of luciferase-transfected HT-1080 cells was colinear with the cell population and the minimal detected cell population was 100 cells/well. Optical imaging showed that the fluorescent intensity of treated group was apparently lower than that of the control. The inhibition rates of lung metastasis by LDM alone at 0.025 mg x kg(-1) and 0.05 mg x kg(-1) were 53.9% and 75.9%, respectively, while that of MTX alone at 0.5 mg x kg(-1) was 70.2%. The combination of LDM at 0.025 mg x kg(-1) and MTX at 0.5 mg x kg(-1) showed an inhibition rate of 88.7%. The coefficient of drug interaction (CDI) was 0.82. The results herein demonstrated that LDM alone had strong anti-metastasis effect on human fibrosarcoma HT-1080 and the inhibition efficacy is strengthened when combined with MTX.
Aminoglycosides ; administration & dosage ; Animals ; Antibiotics, Antineoplastic ; administration & dosage ; Antimetabolites, Antineoplastic ; administration & dosage ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Cell Line, Tumor ; Drug Synergism ; Enediynes ; administration & dosage ; Female ; Fibrosarcoma ; pathology ; Humans ; Luminescent Measurements ; Lung ; pathology ; Lung Neoplasms ; drug therapy ; pathology ; secondary ; Methotrexate ; administration & dosage ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Random Allocation ; Transfection ; Xenograft Model Antitumor Assays

This study is to investigate inhibitory effects of lidamycin (LDM) on the proliferation of HERG K+ channel highly expressing cancer cells and its synergy with anticancer drugs. MTT assay was used to examine the inhibitory effects of lidamycin combined with various anticancer drugs on the proliferation of human lung cancer A549 cells, human colon cancer HT-29 cells and herg-stably-transfected A549 cells. Using the xenograft model of subcutaneously transplanted HT-29 in nude mice, inhibitory effect was appraised in vivo. The coefficient of drug interaction (CDI) was used to evaluate the synergistic effect of drug combination. LDM significantly inhibited the proliferation ofA549 cells and HT-29 cells with IC50 values of 2.14 and 4.64 ng mL(-1), respectively. The efficacy in HT-29 cells with high HERG potassium expression level is less potent than that in A549 cells with low expression level. In terms of IC50 values, LDM suppressed the growth of herg-stably-transfected A549 cells less potently than pCDNA3.1-stably-transfected A549 cells. There existed synergistic effects in the combinations of fluorouracil (5-FU) and LDM, doxorubicin (DOX) and LDM, or hydroxycamptothecine (HCPT) and LDM. CDI values of the combinations of 5-FU and LDM were more than 0.75. CDI values of LDM and DOX were more than 0.70, but some CDI values of LDM and HCPT were less than 0.70. As for the CDI values, synergistic effects of the combination of LDM and HCPT were the most potent of the three groups. There is no relationship between the inhibitory effect of the growth of cancer cells by 5-FU and HERG potassium expression level. HERG expression level negatively correlated with inhibitory effect on the proliferation of cancer cells by DOX. HERG expression levels and chemosensitivity were positively correlated for HCPT. In the model of subcutaneously xenograft transplanted HT-29 in vivo, LDM and/or HCPT effectively inhibited the growth of HT-29 in nude mice, and the optimum CDI of the combination of LDM and HCPT was less than 1. HERG expression level negatively correlates the chemosensitivity of cancer cells to LDM. There exist synergistic effects in vitro and in vivo in the combination of LDM and HCPT, which inhibitory effects of the proliferation of cancer cells positively modulated by HERG potassium expression level. HERG K+ channel may become a target of combined therapy for choosing anticancer drugs.
Aminoglycosides ; administration & dosage ; pharmacology ; Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; Antineoplastic Agents, Phytogenic ; administration & dosage ; Antineoplastic Combined Chemotherapy Protocols ; pharmacology ; Camptothecin ; administration & dosage ; analogs & derivatives ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Doxorubicin ; administration & dosage ; Drug Synergism ; ERG1 Potassium Channel ; Enediynes ; administration & dosage ; pharmacology ; Ether-A-Go-Go Potassium Channels ; metabolism ; Fluorouracil ; administration & dosage ; HT29 Cells ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Xenograft Model Antitumor Assays

OBJECTIVELidamycin (LDM) can be dissociated to an apoprotein (LDP) and an active enediyne chromophore (AE). The detached AE can reassemble with its LDP-containing fusion protein to endow the latter with potent antitumor activity. However, the reassembly of AE with LDP is affected by several factors. Our aim was to optimize the assembly efficiency of the AE with a LDP-containing fusion protein and investigate the influence of several factors on the assembly efficacy.

METHODSA method based on RP-HPLC was developed to analyze the assembly rate, and an orthogonal experimental design L(9) (3(4)) was used to investigate the effects of temperature, assembly time, pH and molecular ratio of LDP-containing fusion protein to AE on the assembly rate. Furthermore, the determined optimum conditions for the assembly rate of the LDP-containing fusion protein with AE were applied and evaluated.

RESULTSA calibration curve based on the LDM micromolar concentration against the peak-area of AE by HPLC was obtained. The order in which individual factors in the orthogonal experiment affected the assembly rate were temperature>time>pH>molar ratio of AE to protein and all were statistically significant (P<0.01). The optimal assembly conditions were temperature at 10°C, time of 12 h, pH 7.0, and the molar ratio of AE: protein of 5:1. The assembly rate of AE with a LDP-containing fusion protein was improved by 23% after condition optimization.

CONCLUSIONThe assembly rate of chromophore of lidamycin with its LDP-containing fusion protein was improved after condition optimization by orthogonal design, and the optimal conditions described herein should prove useful for the development of this type of LDP-containing fusion protein.

Aminoglycosides ; administration & dosage ; chemical synthesis ; chemistry ; pharmacology ; Antibiotics, Antineoplastic ; administration & dosage ; chemical synthesis ; chemistry ; pharmacology ; Apoproteins ; chemistry ; Cell Line, Tumor ; Cell Survival ; Chromatography, High Pressure Liquid ; Drug Design ; Enediynes ; administration & dosage ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Recombinant Fusion Proteins ; chemistry ; Single-Chain Antibodies ; chemistry

This study is to investigate the effect and its possible mechanisms of lidamycin (LDM) combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in human non-small cell lung cancer (NSCLC) cells. MTT assay was used to determine the growth inhibition of the two ingredients on H460 cells. Apoptosis was examined by Annexin V-FITC/PI staining, flow cytometry assay and DNA-specific dye Hoechst 33342 staining. The level of TRAIL receptor and apoptosis-associated protein expression was detected by Western blotting analysis. The results showed that the IC50 value of LDM and TRAIL for H460 cells was 4.603 x 10(-10) mol x L(-1) and 915.3 ng x mL(-1) respectively, but the IC50 value of LDM was 3.064 x 10(-11) mol x L(-1) and 1.611 x 10(-11) mol x L(-1) when different concentrations of LDM was combined with 50 and 100 ng x mL(-1) TRAIL respectively. And the CDI value was less than 1. The apoptosis ratios also increased in the combination group relative to the single-agent treatment and the untreated control. Furthermore, the induction of the cleavage of PARP and the activation of Caspase-3 and Caspase-8 by the combination were more effective than LDM or TRAIL alone. At last, the level of death receptor 5 (DR5) expressions increased in a dose-dependent manner and time-related pattern. The data indicate that LDM inhibits the growth of H460 cells in vitro. DR5 induction contributes to enhancement of TRAIL-induced apoptosis by LDM in human non-small lung cancer cells.
Aminoglycosides ; administration & dosage ; pharmacology ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; Apoptosis ; drug effects ; Carcinoma, Non-Small-Cell Lung ; metabolism ; pathology ; Caspase 3 ; metabolism ; Caspase 8 ; metabolism ; Cell Line, Tumor ; Cell Survival ; drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Enediynes ; administration & dosage ; pharmacology ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Poly(ADP-ribose) Polymerases ; metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; metabolism ; TNF-Related Apoptosis-Inducing Ligand ; administration & dosage ; pharmacology

A nationwide questionnaire-based survey was performed to evaluate the current clinical practices for the management of neutropenic fever in hematology units and hematopoietic stem cell transplantation (HSCT) centers throughout Korea. A 86.9% response rate was obtained from a total of 46 doctors and practical policies of the 33 sites were analysed. Approximately 42.4% and 84.8% of the sites responded that they used oral fluoroquinolone as prophylaxis for neutropenic patients receiving chemotherapy and HSCT, respectively. Additionally, 42.4% of the sites responded that they used antifungal prophylaxis in the chemotherapy groups whereas 90.9% of the sites responded that they used antifungal prophylaxis in HSCT recipients. Approximately half of the responding sites prescribed combination regimen with 3rd or 4th cephalosporin plus aminoglycoside as a first-line therapy. Most of the sites considered persistent fever for 2-4 days or aggravated clinical symptoms for 1-2 days as failure of the first-line regimen, and they changed antibiotics to second- line regimens that varied widely among the sites. Twenty-seven sites (84.4%) responded that they considered adding an antifungal agent when fever persisted for 5-7 days despite antibacterial therapy. Amphotericin B deoxycholate was preferred as a first-line antifungal, which was probably due to the limitations of the national health insurance system. The role of oral antibiotics in the management of neutropenic fever still accounted for a small portion. To the best of our knowledge, this survey is the first report to examine the practical policies currently in place for the management of neutropenic fever in Korea and the results of this survey may help to establish a Korean guideline in the future.
Administration, Oral ; Aminoglycosides/therapeutic use ; Amphotericin B/therapeutic use ; Anti-Bacterial Agents/*therapeutic use ; Antifungal Agents/therapeutic use ; Cephalosporins/therapeutic use ; Data Collection ; Deoxycholic Acid/therapeutic use ; Drug Combinations ; Drug Therapy, Combination ; Fever/*drug therapy/etiology ; Fluoroquinolones/therapeutic use ; Hematopoietic Stem Cell Transplantation ; Humans ; Korea ; Neoplasms/drug therapy ; Neutropenia/*drug therapy ; Prospective Studies ; Questionnaires ; Time Factors ; Treatment Failure

This study was undertaken to evaluate the in vitro activities of arbekacin-based combination regimens against vancomycin hetero-intermediate Staphylococcus aureus (hetero-VISA). Combinations of arbekacin with vancomycin, rifampin, ampicillin-sulbactam, teicoplanin, or quinipristin-dalfopristin against seven hetero-VISA strains and two methicillin-resistant S. aureus strains were evaluated by the time-kill assay. The combinations of arbekacin with vancomycin, teicoplanin, or ampicillinsulbactam showed the synergistic interaction against hetero-VISA strains. Data suggest that these arbekacin-based combination regimens may be useful candidates for treatment options of hetero-VISA infections.
Virginiamycin/administration & dosage ; Vancomycin/*administration & dosage ; Teicoplanin/administration & dosage ; Sulbactam/administration & dosage ; Staphylococcus aureus/*drug effects/isolation & purification ; Staphylococcal Infections/drug therapy/microbiology ; Microbial Sensitivity Tests ; Methicillin Resistance ; Humans ; Drug Synergism ; Drug Resistance, Bacterial ; Dibekacin/administration & dosage/*analogs & derivatives ; Anti-Bacterial Agents/*administration & dosage ; Ampicillin/administration & dosage ; Aminoglycosides/*administration & dosage