Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 15, Issue 1, 2015

Multiresistant Gram-negative bacteria are the prime mover of nosocomial infections. Some are naturally resistant to antibiotics, their genetic makes them insensitive to certain families of antibiotics and they transmit these resistors to their offspring. Moreover, when bacteria are subjected to antibiotics, they eventually develop resistance against drugs to which they were previously sensitive. In recent years, many bacteriocins active against gram-negative bacteria have been identified proving their efficacy in treating infections. While further investigation remains necessary before the possibilities for bacteriocins in clinical practice can be described more fully, this review provides an overview of bacteriocins acting on the most common infectious gram negative bacteria (Klebsiella, Acinetobacter, Pseudomonas aeruginosa and E. coli).

Rabies is a zoonose affecting wild and domestic animals and transmitted to humans through bites or scratches, causing over 60,000 human deaths, annually. The disease results from the transmission of a neurotropic virus leading to invariably deadly encephalitis. The post-exposure prophylaxis consists of careful washing and disinfection of the wound, antibiotherapy and tetanus prophylaxis when needed. Furthermore, rabies vaccine and rabies immunoglobulin [RIG] administration should be applied according to the type of wound, and the animal involved, according to the WHO protocols that are regularly updated. Unfortunately it is sometimes difficult to obtain RIG in some countries due to their high cost, leading to suboptimal treatment and possible death. Also, observance can be weak, due to the number of repeated visits required with protocols [up to five visits over 28 days]. These limitations justify research on new vaccines which were not conclusive at the moment. New RIGs are under development, including a monoclonal antibody cocktail which is more promising in a near future. Finally, vaccination protocols are in the way of being shortened in given conditions. Further studies are needed to validate these new practices.

The present outbreak associated with Ebola disease in Western countries of the African continent which is believed to be one of the massive eruptions caused by the Ebola viral infections. In the present scenario ebola has been transmitted to the European and American regions through the travelers from wide spread countries like Guinea, Liberia, Sierra Leone and Nigeria. The viral disease is spreading through the contact in any form by the infected persons or patients and creating huge risks to the mortals. The symptoms related to ebola virus are often highly pathogenic; about 70-80% of death cases are reported due to critical hemorrhagic fever. Early in infection, ebola virus infects macrophages and endothelial cells. It mainly produces a Viral Protein 24 (eVP24) which prevents interferon-based signals which are important for destruction of viruses. How ebola virus manipulates the function of the immune system is still unclear. Due to lack of this knowledge, no approved treatment is available. In this review, we have tried to compile the epidemiology, pathogenesis and treatment of ebola virus infection. The promising ligands against ebola virus have been also discussed which will be helpful for researchers to design drugs for the treatment of ebola virus disease.

Tuberculosis (TB), a dreadful disease is one of the most important health problems worldwide, and is responsible for approximately 1.3 million death tolls in 2012. DOTS is the currently used drug therapy in TB and the long term drug regimens and patients’ poor compliance lead to emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB, which invigorates the research efforts to address the urgent need for the quick diagnosis and for newer antitubercular agents and vaccines to completely eradicate TB. Today we have at least 20 new diagnostic test platforms, 14 TB vaccine candidates in clinical trials and over 35 candidates in preclinical development, and among the antitubercular agents under clinical investigation, 4 anti-TB agents are in Phase III (efficacy) trials and 7 anti-TB agents are in Phase II, early bactericidal activity and sputum culture conversion trials (rifapentine is in a Phase II and a Phase III trial), 5 anti-TB agents in preclinical development and 3 anti-TB agents in Good Laboratory Practice toxicity evaluation. Recently US FDA has approved TMC207 as a part of combination therapy to treat adults with MDR pulmonary TB in the absence of other alternatives. We provide here the concise review on the chemical entities currently in the clinical trials, the new vaccines in the developmental pipeline, and the new diagnostic test.

Despite therapeutic advances candidiasis remains a common fungal infection most frequently caused by C. albicans and may occur as vulvovaginal candidiasis or thrush, a mucocutaneous candidiasis. Candidiasis frequently occurs in newborns, in immune-deficient people like AIDS patients, and in people being treated with broad spectrum antibiotics. It is mainly due to C. albicans while other species such as C. tropicalis, C. glabrata, C. parapsilosis and C. krusei are increasingly isolated. OTC antifungal dosage forms such as creams and gels can be used for effective treatment of local candidiasis. Whereas, for preventing spread of the disease to deeper vital organs, candidiasis antifungal chemotherapy is preferred. Use of probiotics and development of novel vaccines is an advanced approach for the prevention of candidiasis. Present review summarizes the diagnosis, current status and challenges in the treatment and prevention of candidiasis with prime focus on host defense against candidiasis, advancements in diagnosis, probiotics role and recent progress in the development of vaccines against candidiasis.

Surgery associated with trauma and soft tissue injuries after surgery significantly activates the systemic immune response. If an infection after surgery occurs, the response is even stronger. Due to spontaneous activation of immune response and elevated biomarkers for sepsis and cytokines, posttraumatic complications such as new-coming postoperative infections are difficult to diagnose. Sepsis as systemic inflammatory response syndrome (SIRS) rapidly progresses through severe sepsis to septic shock and organ failure, and with no applied antibiotic treatment, the disease often ends at death of the patients. In the treatment of non-surgery patients, the biomarkers like white cell blood count, Creactive protein (CRP) or procalcitonin (PCT) proved to be useful in sepsis recognition. However, diagnostics after surgeries are more complicated and these biomarkers are not ideal. The solution is a sepsis biomarker, which would have high sensitivity and specificity, that can improve diagnostic accuracy of sepsis, should also be measured easily by the patients, and should not be too expensive. We think more sensitive and specific biomarkers such as presepsin (sCD14-ST) or CD64 index on neutrophils could be useful. A diagnosis of sepsis should be based on clinical signs, and clinicians should use biomarker that is not only most sensitive and specific but also is cost effective. Furthermore, confirmation of the bacterial or fungal infection with blood cultures or with the use of broad range polymerase chain reaction (PCR), when culturing is impossible, should be performed.

Introduction: Serum procalcitonin (PCT) is a biomarker used routinely to diagnose infections. Some malignancies are usual false positives for PCT. However, its value and behavior in the setting of lung cancers are poorly known. The objective of this study was to assess PCT positivity in a lung cancer cases series. Method: Between November 2011 and September 2012, all cases of newly diagnosed lung cancer with a pre-antineoplastic PCT assay and no patent signs of infection were included in the study. All PCT levels were assessed by immunofluorescent assay in a single laboratory. Results: Eighty-nine patients were included (70.8% male; mean age 62; small-cell cancer 20.2%; stage IV cancer 60.7%). Overall, PCT was positive in 42%. A neuroendocrine component, having 2 or more metastatic sites, having a pleura or a liver metastasis, and being positive for CRP were all significantly associated with positive PCT in univariate analysis. In multivariate analysis, only the presence of a neuroendocrine component remained strongly associated with a positive PCT (AOR=7.24 [CI=95% 1.91-27.51]; P=0.004). Finally, baseline PCT levels >0.5 µg/l were found in 43% of NSCLC with a neuroendocrine component, vs. 9% of cancers with other histology (P=0.0001). Conclusion: Lung cancer may cause false positives for procalcitonin, particularly in cases of neuroendocrine cancers or in the presence of multiple metastases. These results should be taken into account for PCT-based decisional algorithms.

Background: ‘Acute lymphoblastic leukemia is the most common childhood malignancy’. Adding methotrexate to treatment protocols increased survival rate in children with leukemia. Methotrexate efficacy is limited by its hepatotoxicity. Aim of the study: To assess the therapeutic value of Black seed oil in ‘methotrexate induced hepatotoxicity in Egyptian children with acute lymphoblastic leukemia’. Subjects and methods: This study was conducted on 40 children with acute lymphoblastic leukemia’ including 20 patients under methotrexate therapy and Black seeds 80mg/kg/day for one week after each methotrexate dose [Group II] and 20 patients under methotrexate therapy and placebo [Group III]. This study included also ‘20 healthy children of matched age and sex as a control group’ [Group I]. All patients were subjected to complete blood picture, bone marrow aspiration and liver functions. Results: No significant differences in liver functions between group II and III before therapy were observed. There were nonsignificant increase in total, direct and indirect serum bilirubin, serum ALT, AST, and alkaline phosphatase levels and prothrombin time in group II after methotrexate and Black seed oil therapy but there was significant increase in group III after treatment with methotrexate and placebo with ‘significant differences between group II and III after therapy. There were significant differences in prognosis regarding remission, relapse, death and ‘disease free survival but no significant difference in overall survival between group II and III’. Conclusion: Black cumin seeds decreased MTX hepatotoxicity and improved survival in children with ALL and can be recommended as adjuvant drug in patients with ALL under methotrexate therapy.