Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 20, Issue 2, 2020

Abdominal tuberculosis is difficult to diagnose due to low sensitivity of microbiological tests and the low histological yield. Satisfactory response to therapy has long been used a criteria for the diagnosis of abdominal tuberculosis. However, the appropriate definitions of response to therapy in abdominal tuberculosis have remained unclear. Recent evidence suggests that mucosal healing of ulcers at the end of therapy or at two months (early mucosal response) is a helpful criteria of response to therapy. This also helps in exclusion of multidrug resistant tuberculosis and alternative diagnosis like Crohn’s disease. Further limited literature suggests the use of some biomarkers like C-reactive protein in the follow-up of patients with peritoneal or intestinal tuberculosis.

Encephalitis caused by Free-living amoebae (FLA) has a mortality rate of around 95- 98%, a fraction that has not changed in the past decades. Pathogenic FLA include Acanthamoeba, Balamuthia mandrillaris, and Naegleria fowleri that are known to target the brain after an extra cerebral infection in the case of Acanthamoeba and Balamuthia mandrillaris, or directly the brain, as in the case of the Naegleria fowleri. The Acanthamoeba spp. and Balamuthia mandrillaris cause granulomatous amoebic encephalitis (GAE) while Naegleria fowleri, the so termed “brain eating amoeba” causes primary amoebic meningoencephalitis (PAM). The attempts to obtain a speedy diagnosis and an aggressive treatment protocol are the areas where advances can make a difference and reduce the mortality rates. At first, we highlight the reasons behind the diagnostic delays and treatment failures and provide proposals to establish a quick diagnosis in both PAM and GAE. Secondly, we emphasize the use of a transcribrial device, and a prompt, but vigilant surgical reduction of the intracranial pressure in these patients which could be life-saving. We also debate that an exudate obtained from the olfactory region by irrigation via a modified transcribrial device or by conventional methods, instead of a cerebrospinal fluid sample, could serve as a source of obtaining amoeba in PAM for a real-time polymerase chain reaction-based definitive diagnosis of PAM. Also, introduced is the rationale that has the potential to deliver the drugs to the brain in patients with PAM and the GAE localized to the frontal lobe of the brain, by bypassing the blood brain barrier. We put forward these proposals for debate and deliberation to our fellow colleagues in order to spot the potential of their application to reduce the mortality rates caused by the rare but fatal encephalitis caused by these FLA.

With the advent of combination antiretroviral therapy (cART), the survival of HIV patients has improved dramatically, but the complications of the disease and treatment have become an important issue in the management of HIV patients. Vitamin-D deficiency is common in HIV patients. Low vitamin-D is associated with different comorbidities in the HIV uninfected general population. In this review, we first briefly describe vitamin D synthesis and mechanism of action and we focus on the epidemiological and clinical data dealing with the relationship between vitamin D deficiency in HIV infection with several comorbidities which has been found to be increasingly common in patients living with HIV infection. We searched the PubMed database using the keywords “HIV,” “vitamin D” and other common disorders or conditions that are relatively common in HIV infection. The other conditions included in the search were osteoporosis and fracture, cardiovascular disease, diabetes and insulin resistance, active tuberculosis, hepatitis-C co-infection, and HIV disease progression. Articles presenting original data as well as systematic reviews and met analysis related to HIV population were included in our analysis. Vitamin-D deficiency seems to be associated with several adverse outcomes in HIV patients but a definite cause and effect relationship with vitamin-D is yet to be confirmed in most of the cases. However, the literature supporting the efficacy of vitamin-D supplementation is lacking.

Background: HCV treatment showed dramatical change due to the introduction of potent, strong, direct antiviral drugs. Before the appearance of Direct-acting antivirals, multiple therapeutic interventions were used for hepatitis C, but none of these interventions were effective on patient-centered outcomes. Direct-acting antivirals cause disruption of viral replication because they target specific nonstructural viral proteins. Aim: To review the advantages of efficient HCV therapy and its long term drawbacks. Methods: A search of the literature published in indexed databases (PubMed, Medline In-Process, and Embase) within the last 5 years was conducted. Any duplicated citations were excluded before first-pass screening. Citations (titles and abstracts) were screened for eligibility by a single reviewer. Full texts (including congress abstracts, posters and other congress communications) of citations deemed relevant during title and abstract screening were retrieved for second-pass review. Results: Studies on the clinical effects of DAAs for hepatitis C show better tolerance, improved survival and fewer complications when compared to previous interferon therapy. Conclusion: HCV treatment has improved dramatically. Since that time, there are multiple approved oral therapies all with high efficacy. The most important factor which should be considered during choosing appropriate therapy is to ensure that it covers the viral genotype of the infected patients.

Background: In the current study, we present an integrated in silico cheminformaticsmolecular docking approach to screen and test potential therapeutic compounds against viruses. Fluoroquinolones have been shown to inhibit HCV replication by targeting HCV NS3-helicase. Based on this observation, we hypothesized that natural analogs of fluoroquinolones will have similar or superior inhibitory potential while having potentially fewer adverse effects. Methods: To screen for natural analogs of fluoroquinolones, we devised an integrated in silico Cheminformatics-Molecular Docking approach. We used 17 fluoroquinolones as bait reference, to screen large databases of natural analogs. 10399 natural compounds and their derivatives were retrieved from the databases. From these compounds, molecules bearing physicochemical similarities with fluoroquinolones were analyzed using a cheminformatics-docking approach. Results: From the 10399 compounds screened using our cheminformatics approach, only 20 compounds were found to share physicochemical similarities with fluoroquinolones, while the remaining 10379 compounds were physiochemically different from fluoroquinolones. Molecular docking analysis showed 32 amino acids in the HCV NS3 active site that were most frequently targeted by fluoroquinolones and their natural analogues, indicating a functional similarity between the two groups of compounds. Conclusion: This study describes a speedy and inexpensive approach to complement drug discovery and design against viral agents. The in silico analyses we used here can be employed to shortlist promising compounds/putative drugs that can be further tested in wet-lab.

Background: Salmonellosis is a major food-borne disease worldwide. The increasing prevalence of antimicrobial resistance among food-borne pathogens such as Salmonella spp. is concerning. Objective: The main objective of this study is to identify class 1 integron genes and to determine antibiotic resistance patterns among Salmonella isolates from children with diarrhea. Methods: A total of 30 Salmonella isolates were recovered from children with diarrhea. The isolates were characterized for antimicrobial susceptibility and screened for the presence of class 1 integron genes (i.e. intI1, sulI1, and qacEΔ1). Results: The most prevalent serotype was Enteritidis 36.7%, followed by Paratyphi C (30%), and Typhimurium (16.7%). The highest rates of antibiotic resistance were obtained for nalidixic acid (53.3%), followed by streptomycin (40%), and tetracycline (36.7%). Regarding class 1 integrons, 36.7%, 26.7%, and 33.3% of the isolates carried intI1, SulI, and qacEΔ1, respectively, most of which (81.8%) were multidrug-resistant (MDR). Statistical analysis revealed that the presence of class 1 integron was significantly associated with resistance to streptomycin and tetracycline (p = 0.042). However, there was no association between class 1 integron and other antibiotics used in this study (p > 0.05). Conclusion: The high frequency of integron class 1 gene in MDR Salmonella strains indicates that these mobile genetic elements are versatile among different Salmonella serotypes, and associated with reduced susceptibility to many antimicrobials.

Background: Lymphatic filariasis (LF) is a parasitic disease that has been targeted for elimination through the Mass Drug Administration (MDA.) Although the MDA started in the Ankobra community in Ghana in 2000, LF prevalence as reported in 2014 was relatively high (4.5%). Non-compliance to the MDA has been associated with the persistent LF prevalence in endemic regions. Objective: This study determined the factors associated with the non-compliance to the MDA among patients living in the Ankobra community, Ghana. Methods: A cross-sectional study using a one-stage cluster sampling method was used to collect data between June and July, 2017 in Ankobra. Questionnaires were used to collect data from health workers, the MDA drug distributors and study participants in Ankobra. Data analysis was performed using STATA 14. Logistic regression was used to measure the degree of association between the dependent (non-compliance) and independent variables. Non-compliance rate was defined as the percentage of individuals who self-reported that they did not actually swallow the drugs provided during the MDA. Results: The MDA coverage and non-compliance rates were 73.5% (147/200) and 33.33% (49/147) respectively. The main reason for non-compliance was fear of drug adverse events (75.51%, 37/49). Thought of “not being susceptible to LF” was significantly associated with the non-compliance (aOR= 2.83, [CI= 1.15, 6.98]). Conclusion: Health education about the susceptibility of residents getting LF disease in endemic community must be intensified to improve compliance to MDA medication ingestion and thus meet the Global Elimination of Lymphatic Filariasis by 2020.

Background: Tumor necrosis factor and its receptors (sTNFR1 and sTNFR2) have been implicated in many infectious diseases. Identification of the key receptor (sTNFR1 or sTNFR2) which drives the immunopathogenesis of HIV infection is crucial in developing adjunctive therapy for HIV. Objective: This study determined the expression levels of sTNFR1 and sTNFR2 in antiretroviral therapy (ART) - experienced and naïve HIV patients. Methods: A total of 40 HIV patients comprising 30 with ART and 10 without ART were enrolled from the Pantang Hospital located in the Greater Accra Region of Ghana for data and blood collection. Serum concentrations of sTNFR1 and sTNFR2 were determined by ELISA. Mann- Whitney U test was used to examine differences in serum levels of sTNFR1 and sTNFR2 between patients on ART and ART naïve patients. Wilcoxon Signed-Rank test was performed to determine the difference between sTNFR1 and sTNFR2, and Kruskal Wallis test was conducted to compare the effect of different antiretroviral drugs on the levels of sTNFR1 and sTNFR2. P< 0.05 was considered statistically significant. Results: A Wilcoxon Signed-Ranks Test indicated serum levels of sTNFR2 was statistically significantly higher than sTNFR1 (Z=-5.51; p<0.001). Levels of sTNFR1 and sTNFR2 did not differ by ART status U =91.00 (Z = -1.84), p = 0.065 and U = 131.50 (Z = -0.58, p =0.560), respectively. There were not significant differences in levels of TNFR2 H(2) = 1.86, p=0.395 and sTNFR1 (H (2) = 4.37, p=0.113 across different ART combinations. Conclusion: Compared to sTNFR1, the level of sTNFR2 is significantly increased during HIV infection irrespective of ART status. The high sTNFR2 level is not associated with antiretroviral drugs and may be another potential target for therapeutic development. This is the first study of sTNFRs in African population.

Background: The emergence of infectious diseases and its resistance to approved drugs is a global threat to human health. The incidence of infectious diseases is increasing day by day and expected to rise exponentially in next 2 decades. Thus, there is a need for new treatment modalities for the treatment of microbial infections. Methods: Thus, in the current investigation, we have explored the existing drugs [metformin (Anti-diabetic), propranolol (Anti-hypertensive) and amitriptyline (antidepressant)] for treatment of infectious diseases. Results: An in-silico result of current investigation has shown the good interaction of metformin, propranolol, and amitriptyline towards various targets (Beta-lactamase, Penicillin-binding proteins, Staphylokinase protein, Oxidoreductase protein, etc.) of gram positive and gram negative bacteria as that of internal ligand. Further, in-vitro results have shown that the antibacterial activity of metformin, propranolol, and amitriptyline against Bacillus pumilus, Pseudomonas aeruginosa and Staphylococcus aureus. Conclusion: The parameters such as Microtiter assay: percentage growth retardation and bacterial growth kinetics, Minimum inhibitory concentration (MIC), Post-antibiotic assay and Biofilm formation have indicated the antibacterial potential of metformin, propranolol, and amitriptyline. However, before starting a clinical trial, complete safety and efficacy profile of drugs in the treatment of infectious diseases should be investigated.

Introduction: Infertility considered as a social and public health issue and estimated that most of these infertile couples are residents of developing countries. Infectious diseases including the history of Sexually Transmitted Infections (STIs) may impact on male reproductive function. Therefore, the present study aimed to investigate the prevalence of bacterial contaminants of semen and probable association with sperm quality of infertile men in Iranian population. Methods: The study population consisted of 200 infertile men and 150 fertile men attending an infertility Center in southwestern Iran during the study period in 2015. The assessment of sperm parameters was according to the World Health Organization (WHO) guidelines. The presumptive pathogens were identified using standard microbiology tests and confirmed by specific PCR primers. Results: The prevalence of bacteriospermia in the semen of the infertile group was significantly higher than that in the fertile group (48% vs. 26.7%, P <0.001). The microbiological analysis of samples showed that the most abundant species of bacteria in semen of infertile men were Chlamydia trachomatis (12.5%) followed by Neisseria gonorrhoeae (11%). On the other hand, in the control group, Lactobacillus spp. (17.3%) was the most isolated pathogen. Results showed that the presence of N. gonorrhoeae, C. trachomatis, Mycoplasma genitalium, Haemophilus, and Klebsiella was significantly associated with sperm abnormality. Conclusions: Based on our findings, it seems that bacteriospermia is associated with alterations in the properties of semen which may lead to a decrease in the fertilization potential of sperm. Therefore, immediate and appropriate treatment is necessary before investigating every other possible cause of infertility.

Introduction: Incidence of brucellosis was growing up in Iran during the past years. Kermanshah province-west of Iran is one of the endemic regions of the disease. The aim of this study was to evaluate the incidence and risk factors of brucellosis in Kermanshah province during a recent five-year period. Methods: This study was an observational cross-sectional study performed on registries of the patients with brucellosis at the center for the zoonotic disease of Kermanshah University of medical sciences during 2010-2014. The data was collected using a questionnaire containing demographic data and the risk factor of brucellosis. Collected data were analyzed by SPSS-22 software using descriptive statistic, Chi-square, and student t-test. Results: The five-years mean incidence of brucellosis in our study was 46.5 in one hundred thousand, and male to female ratio was 1.37/1. The most common risk factors of brucellosis in our patients were unpasteurized dairy products’ consumption (47%) and occupational contact with livestock (14.4%). 84% of the patients were rural. The most common diagnostic method was the standard agglutination test within 1/160 and 1/320 titers. Conclusion: Risk factors of brucellosis in our study were like other studies, but in more than onethird of the patients, no risk factor was identified. Lack of livestock vaccination history and incomplete registered data about other possible transmission routes of transmission were the limitations of the study.

Background: Imidazole is one of the most explored and marketed azole utilized for the treatment of fungal infections. Lanosterol 14α-demethylase (Cytochrome P450DM) is the active target site for azole antifungals. Aim and Objective: This study emphasized on evaluation of a series of halogenated imidazole analogues using molecular docking studies for anti-Candidal activity. Furthermore, the model was refined by molecular dynamic simulation. Methods: Halogenated imidazole analogues (PS1-PS30) were obtained from literature for the study. The imidazole analogues were prepared using Chem sketch and molecular docking was performed using Molergo Virtual Docker program and ADMET study was carried out by using Accelry’s Accord for Excel programme. Results: The docking study indicated that all the imidazole analogues (PS1-PS30) and standard drugs i.e., Ketoconazole, Miconazole and Clotrimazole possessed interaction with protein residue, heme cofactor and water molecule positioned above Heme cofactor of 14α-demethylase. Further, the ADMET study indicated that most of the halogenated imidazoles possessed good absorption, human intestinal absorption, aqueous solubility and blood brain penetration. Conclusion: Halogenated imidazole analogues may be used as potential lead molecules as 14α- demethylase inhibitors.

Aims and Objectives: The present work aimed to evaluate the frequency of aminoglycoside- modifying enzymes encoding genes in the E. faecalis and E. faecium and their antibiotic resistance profile. Methods: A total of 305 different clinical samples were subjected for identification and antibiotic susceptibility test. The high-level aminoglycoside resistance was identified by MIC and Kirby Bauer disc diffusion method. The prevalence of aac (6')-Ie-aph (2'')-Ia, aph (3')-IIIa and ant (4')- Ia genes was determined by multiplex- PCR. In total, 100 enterococci strains were isolated. The prevalence of E. faecalis and E. faecium isolates was 78% and 22%, respectively. Results: All isolates were susceptible to linezolid. So, all E. faecalis were susceptible to vancomycin but, 36.4% of E. faecium were resistant to it. The prevalence of multiple drug resistance strains was 100% and 67.9% of E. faecium and E. faecalis, respectively. High-level-gentamicin and streptomycin resistant rates were as follows; 26.9% and 73.1% of E. faecalis and 77.3% and 90.1% of E. faecium. Conclucion: The results of the current study showed a high frequency of aac (6')-Ie-aph (2'')-Ia genes among enterococcal isolates. A high rate of resistance to antimicrobials in Enterococcus is obviously problematic, and a novel policy is needed to decrease resistance in these microorganisms.

Objectives: The study aimed to describe the identity and antimicrobial resistance patterns of the causative agents of bacterial meningitis in children referred to Children’s Medical Center (CMC) Hospital, Tehran, Iran. Methods: This retrospective study was performed at CMC Hospital during a six-year period from 2011 to 2016. The microbiological information of the patients with a diagnosis of bacterial meningitis was collected and the following data were obtained: patients’ age, sex, hospital ward, the results of CSF and blood cultures, and antibiotic susceptibility profiles of isolated organisms. Results: A total of 118 patients with bacterial meningitis were admitted to CMC hospital. Sixty-two percent (n=73) of the patients were male. The median age of the patients was ten months (interquartile range [IQR]: 2 months-2 years) and the majority of them (n=92, 80%) were younger than two years of age. The highest number of patients (n=47, 40%) were admitted to the surgery department. Streptococcus epidermidis was the most frequent isolated bacterium (n=27/127, 21%), followed by Klebsiella pneumoniae (n=20/127, 16%), and Staphylococcus aureus (n=16/127, 12.5%). Blood culture was positive in 28% (n=33/118) of patients. Ampicillin-sulbactam and imipenem were the most effective antibiotics against Gram-negative bacteria isolated from CSF cultures. In the case of Gram-positive organisms, ampicillinsulbactam, vancomycin, and linezolid were the best choices. Imipenem was the most active drug against Gram-negative blood pathogens. Also, ampicillin and vancomycin had the best effect on Gram-positive bacteria isolated from blood cultures. Conclusion: Results of this study provide valuable information about the antibiotic resistance profiles of the etiologic agents of childhood meningitis, which can be used for prescription of more effective empirical therapies.

Methods: A series of 1-{2-(prop-2-ynyloxy)aryl}-3-hydroxy-3-(4'-trifluoromethylphenyl) prop-2-en-1-ones obtained by photo-irradiation of 2-{2-(prop-2-ynyloxy)benzoyl}-3-(4- trifluorome-thyl-phenyl)oxiranes (that were characterized by spectral studies: FT-IR, 1H NMR, 13C NMR and Mass analysis) was screened for the anti-malarial activity by evaluating against chloroquine-sensitive P. falciparum (CD7). The molecular docking studies using AutoDock Vina were also performed to further ascertain the efficacy of these compounds with PDB:4ORM. Results: Among these, the hydroxyenone derivatives 2b, 2c and 2a exhibited very potent antimalarial activity that was clearly evinced by the results of molecular docking. Binding energies of hydroxyenone compounds were calculated and found in the range of -10.4 to -9.0 kcal/mol. Conclusion: Compound 2b had the strongest binding affinity with docking score of -10.4 kcal/mol.

Background Context: Chronic Suppurative Otitis Media (CSOM) is a common cause of hearing impairment and disability. CSOM caused by Pseudomonas aeruginosa is usually treated with topical ciprofloxacin and resistance to ciprofloxacin in CSOM isolates has rarely been reported. Case Presentation: A 24-year-old male patient with CSOM due to p. aeruginosa was reported. CSOM was prolonged for ten years and physician prescribed topical ciprofloxacin drops, pus suctioning and ear pH alteration. The treatment wasn’t effective and the patient came back to the clinic with relapse of suppurative otitis media. P. aeruginosa was isolated as the cause of CSOM and the isolate was resistant to ciprofloxacin, aztreonam, imipenem, gentamicin, doripenem, cefepime, levofloxacin, amikacin and susceptible to colistin and ceftazidime. There were two mutations in gyrA and eight mutations were observed in nfxB genes. Finally, tympanomastoidectomy was done. Conclusion: Usually topical antibiotics, especially ciprofloxacin, is effective against ear infections but our case was different and the P. aeruginosa isolated from CSOM was resistant to most of the antibiotics. One reason for CSOM recurrence might be surgery failure. The routine and primary treatment for CSOM did not seem sufficient and tympanomastoidectomy is suggested to be the best treatment approach for these patients.

L. pneumophila is an unusual cause of pneumonia with a prevalence of 2.7%, and it is even more uncommon in pregnancy. To date, only 11 cases of Legionnaire’s Disease in pregnancy have been reported, though this small number could possibly be attributed to underdiagnoses and under documentation. Case Presentation: In this paper, we present a 31-year-old Hispanic female, gravida 4, para 1 from the southwest United States who presented with a 3-week history of fever, worsening cough, dyspnea on exertion, and hypoxemia. Chest x-ray showed bibasilar infiltrates, with positive serology for Legionella IgM and IgG (1:250 and 1:640 respectively), as well as positive urinary antigen. Despite appropriate treatment with azithromycin 500 mg, she continued to have dyspnea and mild respiratory distress. Conclusion: Upon follow up, mother and fetus initially remained stable without any signs of sequelae from Legionnaire’s disease, but the patient miscarried 5 weeks after the second admission to the hospital. The chest x-ray eventually cleared up after almost 21 days of azithromycin.

Allopurinol is an FDA -Approved xanthine oxidase inhibitor, which is effective in the treatment of gout, hyperuricemia and uremic kidney stones in patients with an increased level of uric acid excretion. Xanthine oxidase acts by converting hypoxanthine and xanthine into uric acid, and therefore its inhibition results in decreased production of uric acid. The most common side effects of this medication are as follows: maculopapular rashes, hives, itching, headache, dizziness, abnormal hair loss, fever and hypersensitivity reaction. Case Presentation: This report represents a case of drug-induced meningitis of a senile man who ended up in the ICU due to the remarkably reduced state of consciousness.