Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged to be one of the world's greatest health threats. However, not only have recent decades shown a steady decline in the number of approved antimicrobial agents but a disappointing discovery also void. The development of novel antibiotics to treat MDR Gram-negative bacteria has been stagnated over the last half century. Though few compounds have shown activities in vitro, in animal models or even in clinical studies, the global antibiotic pipeline is not encouraging. There are a plethora of unexpected challenges that may arise and cannot always be solved to cause promising drugs to fail. This review intends to summarize recent research and development activities to meet the inevitable challenge in restricting the proliferation of MDR Gram-negative bacteria, with focus on compounds that have entered into clinical development stage. In addition to new analogues of existing antibiotic molecules, attention is also directed to alternative strategies to develop antibacterial agents with novel mechanisms of action.
Aminoglycosides ; pharmacology ; therapeutic use ; Animals ; Anti-Bacterial Agents ; pharmacology ; therapeutic use ; Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Drug Discovery ; Drug Resistance, Multiple, Bacterial ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Ferrous Compounds ; pharmacology ; therapeutic use ; Gram-Negative Bacteria ; drug effects ; Gram-Negative Bacterial Infections ; drug therapy ; Humans ; Peptides ; pharmacology ; therapeutic use ; Peptidomimetics ; pharmacology ; therapeutic use ; Tetracyclines ; pharmacology ; therapeutic use ; beta-Lactamase Inhibitors ; beta-Lactams ; pharmacology ; therapeutic use

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

BACKGROUND/AIMS: The spectrum of Clostridium difficile-associated disease (CDAD) ranges from mild diarrhea to life-threatening colitis. Recent studies reported an increase in incidence and severity of CDAD and the presence of severe community-acquired CDAD (CA-CDAD). The aims of this study were to investigate the incidence of CA-CDAD and non-antibiotics-associated CDAD, and to compare the clinical characteristics between hospital-acquired (HA) and CA-CDAD. METHODS: The medical records of 86 patients who were diagnosed as CDAD in Hanyang University Guri Hospital between January 2005 and October 2007 were retrospectively reviewed. RESULTS: Of the 86 patients (mean age 64 years), 53 patients were women. The most frequently prescribed antibiotics were cephalosporins (67.4%), followed by aminoglycosides (38.4%) and quinolones (14%). Of the 86 patients, the average duration of treatment and recovery time of symptoms were 11.5 days and 4.6 days, respectively. Seven percent of patients experienced relapse treatment. The overall incidence rate of CA-CDAD and non-antibiotics-associated CDAD were 10.5% and 22.1%, respectively. CA-CDAD group had lower rate of antimicrobial exposure whilst showing higher rate of complications compared to HA-CDAD group. Three patients in the CA-CDAD progressed towards a severe complicated clinical course, including septic shock. CONCLUSIONS: The incidence rate of CA-CDAD and non-antibiotics-associated CDAD were 10.5% and 22.1%, respectively. CA-CDAD tends to have a higher complication rate compared to HA-CDAD. Community clinicians needs to maintain a high level of suspicion for CDAD, whilst coping with the ever evolving epidemiologic change.
Adult ; Aged ; Aged, 80 and over ; Aminoglycosides/therapeutic use ; Anti-Bacterial Agents/therapeutic use ; Bacterial Toxins/analysis ; Cephalosporins/therapeutic use ; *Clostridium difficile ; Community-Acquired Infections/epidemiology ; Cross Infection/epidemiology ; Enterocolitis, Pseudomembranous/*diagnosis/drug therapy/epidemiology ; Enterotoxins/analysis ; Female ; Humans ; Male ; Metronidazole/therapeutic use ; Middle Aged ; Quinolones/therapeutic use ; Retrospective Studies

Antibiotics are widely used in the treatment of premature low birth-weight babies, either as blind therapy before infection is confirmed or, more specifically against a pathogen of known antibiotic susceptibility. The requirements of an antibiotic for use in the newborn are different from those in older patients and in almost every respect there are differences in the pharmacology and pharmacokinetics of antibiotics in the very young. A wide range of bacteria are responsible for infection in the new born and the distribution of these organisms will vary not only from country to country, but also from hospital to hospital. Antibiotics in current use are less effective against bacteria infecting the newborn than they once were and the introduction of new antibiotics, notably the third generation cephalosporins, provides an opportunity to reassess current antibiotic practices. This paper outlines the general considerations for chemotherapy in small babies and attempts to identify those areas where a review of current antibiotic practice is required. It is essential that decisions regarding antibiotic policies for neonatal units should be made locally and that they reflect local experience and the range of pathogens most frequently encountered and their sensitivity patterns.
Aminoglycosides ; therapeutic use ; Anti-Bacterial Agents ; metabolism ; therapeutic use ; toxicity ; Bacterial Infections ; drug therapy ; Drug Administration Schedule ; Humans ; Infant, Newborn ; Infant, Premature, Diseases ; drug therapy ; Kinetics ; Microbial Sensitivity Tests ; Risk ; Time Factors

This study is to investigate the antitumor activities of the immunoconjugates composed of anti-type IV collagenase monoclonal antibody 3G11 and lidamycin (LDM) prepared by different methods. The immunoconjugates were prepared by linking 2-iminothiolane modified 3G11 to lysine-69 of LDM apoprotein by SPDP and SMBS as the intermediate drug linker. Immunoreactivity of the conjugates was determined by ELISA. The cytotoxicity of the conjugates was examined by clonogenic assay. Antitumor effects of the conjugates in vivo were evaluated in nude mice bearing subcutaneously implanted HT-1080 tumor. ELISA assay showed that the immunoconjugates retained the immunoreactivity of 3G11 against type IV collagenase. The cytotoxicity of the 3G11-SMBS-LDM to HT-1080 cells was significantly more potent than that of free LDM and 3G11-SPDP-LDM. In animal model at the same condition, free LDM inhibited the growth of HT-1080 tumor by 71.2%, while 3G11-SPDP-LDM and 3Gl1-SMBS-LDM reached 77.1% and 86.1%, respectively. The median survival time of the mice treated with free LDM was prolonged by 71.9% compared with that of untreated group. Whereas, the median survival time of 3G11-SPDP-LDM and 3G11-SMBS-LDM was prolonged by 125.3% and 163.7%, respectively, indicating that 3G11-SMBS-LDM was more effective than 3G11-SPDP-LDM in tumor suppression and life span prolongation. 3Gll-SMBS-LDM has more selective antitumor efficacy and lower toxicity, and might be a novel candidate for cancer therapy. LDM was more effective than 3G11-SPDP-LDM in tumor suppression and life span prolongation. 3Gll-SMBS-LDM has more selective antitumor efficacy and lower toxicity, and might be a novel candidate for cancer therapy.
Aminoglycosides ; therapeutic use ; Animals ; Antibiotics, Antineoplastic ; therapeutic use ; Antibodies, Monoclonal ; immunology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Collagenases ; immunology ; Enediynes ; therapeutic use ; Fibrosarcoma ; pathology ; therapy ; Humans ; Immunoconjugates ; therapeutic use ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Tumor Burden ; drug effects

AIMTo study the antitumor effects of an immunoconjugate composed of lidamycin (LDM) and monoclonal antibody 3G11 (3G11-LDM conjugate).

METHODS3G11-LDM conjugate was prepared by using 2-iminothiolane (2-IT) and m-maleimidobenzoyl-N-hydroxy-succimide ester (MBS) as crosslinkers. The molecular weight of the conjugate was measured on non-reduced SDS-PAGE gel. Immunoreactivity of 3G11-LDM conjugate to type IV collagenase or to hepatoma 22 cells was determined by ELISA. The cytotoxicity of the immunoconjugate to hepatoma 22 cells was examined by MTT assay. Antitumor effects of the 3G11-LDM conjugate in vivo were evaluated using subcutaneously transplanted hepatoma 22 tumor model in mice.

RESULTSThe molecular weight of 3G11-LDM conjugate was approximately 160 kDa. 3G11-LDM conjugate retained part of the immunoreactivity of 3G11 to type IV collagenase and hepatoma 22 cells. As compared with free LDM, 3G11-LDM conjugate showed stronger cytotoxicity to hepatoma 22 cells. When administered intravenously (i.v. x 2 on day 1 and 8), 3G11-LDM conjugate, at doses of 0.05 and 0.10 mg.kg-1, inhibited the growth of hepatoma 22 in mice by 87.8% and 97.2% on day 11, respectively, whereas the unconjugated LDM at 0.05 mg.kg-1 inhibited tumor growth by 67.1%. The median survival times for tumor-bearing mice of untreated control, LDM at 0.05 mg.kg-1, 3G11-LDM at 0.05 mg.kg-1, and 3G11-LDM at 0.10 mg.kg-1 were 34, 41.5, 60.5 and 94 d, respectively. Evidently 3G11-LDM was more effective than free LDM in suppressing tumor growth and prolonging the life span of tumor-bearing mice.

CONCLUSION3G11-LDM conjugate shows much stronger antitumor effects than equivalent dose of free LDM and may have promising therapeutic potential in cancer treatment.

Aminoglycosides ; administration & dosage ; therapeutic use ; Animals ; Antibiotics, Antineoplastic ; administration & dosage ; therapeutic use ; Antibodies, Monoclonal ; immunology ; Cell Division ; drug effects ; Disease Models, Animal ; Enediynes ; Female ; Immunoconjugates ; therapeutic use ; Liver Neoplasms, Experimental ; drug therapy ; pathology ; Matrix Metalloproteinase 2 ; immunology ; Matrix Metalloproteinase 9 ; immunology ; Mice ; Neoplasm Transplantation ; Random Allocation ; Tumor Cells, Cultured

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