Antibody-Antibiotic Conjugates: A Comprehensive Review on Their Therapeutic Potentials Against BacterialInfections.

INTRODUCTION: Antibodies are significant agents in the immune system and have proven to be effective in treating bacterial infections. With the advancement of antibody engineering in recent decades, antibody therapy has evolved widely. AIM: This review aimed to investigate a new method as a therapeutic platform for the treatment of bacterial infections and explore the novel features of this method in conferring pathogen specificity to broad-spectrum antibiotics. MATERIAL AND METHODS: A literature review was conducted addressing the following topics about antibody-antibiotic conjugates (AACs): (1) structure and mechanism of action; (2) clinical effectiveness; (3) advantages and disadvantages. RESULT: Antibody conjugates are designed to build upon the progress made in the development of monoclonal antibodies for the treatment of diseases. Despite the growing emergence of antibiotic resistance among pathogenic bacteria worldwide, novel antimicrobials have not been sufficiently expanded to combat the global crisis of antibiotic resistance. A recently developed strategy for the treatment of infectious diseases is the use of AACs, which are specifically activated only in host cells. CONCLUSION: A novel therapeutic AAC employs an antibody to deliver the antibiotic to the bacteria. The AACs can release potent antibacterial components that unconjugated forms may not exhibit with an appropriate therapeutic index. This review highlights how this science has guided the design principles of an impressive AAC and discusses how the AAC model promises to enhance the antibiotic effect against bacterial infections.

Tigecycline antibacterial activity, clinical effectiveness, and mechanisms and epidemiology of resistance: narrative review.

Tigecycline is unique glycylcycline class of semisynthetic antimicrobial agents developed for the treatment of polymicrobial infections caused by multidrug-resistant Gram-positive and Gram-negative pathogens. Tigecycline evades the main tetracycline resistance genetic mechanisms, such as tetracycline-specific efflux pump acquisition and ribosomal protection, via the addition of a glycyclamide moiety to the 9-position of minocycline. The use of the parenteral form of tigecycline is approved for complicated skin and skin structure infections (excluding diabetes foot infection), complicated intra-abdominal infections, and community-acquired bacterial pneumonia in adults. New evidence also suggests the effectiveness of tigecycline for the treatment of severe Clostridioides difficile infections. Tigecycline showed in vitro susceptibility to Coxiella spp., Rickettsia spp., and multidrug-resistant Neisseria gonnorrhoeae strains which indicate the possible use of tigecycline in the treatment of infections caused by these pathogens. Except for intrinsic, or often reported resistance in some Gram-negatives, tigecycline is effective against a wide range of multidrug-resistant nosocomial pathogens. Herein, we summarize the currently available data on tigecycline pharmacokinetics and pharmacodynamics, its mechanism of action, the epidemiology of tigecycline resistance, and its clinical effectiveness.

Effect of probiotic supplementation on migraine prophylaxis: a systematic review and meta-analysis of randomized controlled trials.

Objective: The prevalence of migraine is higher in patients with gastrointestinal disorders. Possible underlying mechanisms could be increased intestinal permeability and systemic inflammation. Probiotics may reduce gut permeability as well as inflammation, and therefore may improve the clinical features of migraine. This systematic review and meta-analysis aimed to evaluate the impact of probiotic supplementation on the frequency and severity of migraine attacks.Methods: A systematic review of the literature was conducted using ISI Web of Science, PubMed/Medline, Scopus, Cochrane Library, EMBASE, Google Scholar, Magiran.com and Sid.ir to identify eligible studies published up to October 2019. A meta-analysis of eligible trials was performed using the random-effects model to estimate pooled effect size.Results: Three randomized controlled trials with 179 patients (probiotic group = 94, placebo group = 85) were included. Probiotic supplementation had no significant effect on frequency (weighted mean difference (WMD) = -2.54 attacks/month, 95%CI: -5.31-0.22, p = 0.071) and severity of migraine attacks (WMD = -1.23 visual analog scale (VAS) score, 95%CI = -3.37-0.92, p = 0.262) with significant heterogeneity among the studies (I2 = 98%, p < 0.001).Conclusions: A pooled analysis of available randomized controlled clinical trials showed that probiotic supplementation had no significant effect on the frequency and severity of episodic migraine attacks.

Environmental Surface Circulation of SARS-CoV-2 RNA in Asadabad Hospital Wards.

BACKGROUND: Since early 2020, Coronavirus 2019 (COVID-19) has posed a public health risk due to serious acute respiratory syndrome. The aim of our study was to determine surface circulation of SARS-CoV-2 RNA in Asadabad Hospital wards. METHODS: Fifty swab samples were obtained from the hospital wards. The real-time test was carried out using primer/probe sets that were complementary to targets on the SARS CoV genome. RESULTS: The injection room had the highest contamination rate, while the other hospital wards were free of CO¬VID-19 contamination. CONCLUSIONS: Overall, we found that COVID-19 contaminated narrowly the surfaces in hospital wards. These findings can be used to improve safety procedures.

Potential drugs used in the antibody-drug conjugate (ADC) architecture for cancer therapy.

Cytotoxic small-molecule drugs have a major influence on the fate of antibody-drug conjugates (ADCs). An ideal cytotoxic agent should be highly potent, remain stable while linked to ADCs, kill the targeted tumor cell upon internalization and release from the ADCs, and maintain its activity in multidrug-resistant tumor cells. Lessons learned from successful and failed experiences in ADC development resulted in remarkable progress in the discovery and development of novel highly potent small molecules. A better understanding of such small-molecule drugs is important for development of effective ADCs. The present review discusses requirements making a payload appropriate for antitumor ADCs and focuses on the main characteristics of commonly-used cytotoxic payloads that showed acceptable results in clinical trials. In addition, the present study represents emerging trends and recent advances of payloads used in ADCs currently under clinical trials.

How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment?

Exosomes, as natural occurring vesicles, play highly important roles in the behavior and fate of ischemic diseases and different tumors. Secretion, composition, and function of exosomes are remarkably influenced by hypoxia in ischemic diseases and tumor microenvironment. Exosomes secreted from hypoxic cells affect development, growth, angiogenesis, and progression in ischemic diseases and tumors through a variety of signaling pathways. In this review article, we discuss how hypoxia affects the quantity and quality of exosomes, and review the mechanisms by which hypoxic cell-derived exosomes regulate ischemic cell behaviors in both cancerous and noncancerous cells.

Risk factors for mortality in patients with Coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of observational studies.

PURPOSE: Coronavirus disease 2019 (COVID-19) is an emerging disease that was first reported in Wuhan city, the capital of Hubei province in China, and has subsequently spread worldwide. Risk factors for mortality have not been well summarized. Current meta-analysis of retrospective cohort studies was done to summarize available findings on the association between age, gender, comorbidities and risk of death from COVID-19 infection. METHODS: Online databases including Web of Science, PubMed, Scopus, Cochrane Library and Google scholar were searched to detect relevant publications up to 1 May 2020, using relevant keywords. To pool data, random-effects model was used. Furthermore, sensitivity analysis and publication bias test were also done. RESULTS: In total, 14 studies with 29,909 COVID-19 infected patients and 1445 cases of death were included in the current meta-analysis. Significant associations were found between older age (≥65 vs <65 years old) (pooled ORs = 4.59, 95%CIs = 2.61-8.04, p < .001), gender (male vs female) (pooled ORs = 1.50, 95%CIs = 1.06-2.12, p = .021) and risk of death from COVID-19 infection. In addition, hypertension (pooled ORs = 2.70, 95%CIs = 1.40-5.24, p = .003), cardiovascular diseases (CVDs) (pooled ORs = 3.72, 95%CIs = 1.77-7.83, p = .001), diabetes (pooled ORs = 2.41, 95%CIs = 1.05-5.51, p = .037), chronic obstructive pulmonary disease (COPD) (pooled ORs = 3.53, 95%CIs = 1.79-6.96, p < .001) and cancer (pooled ORs = 3.04, 95%CIs = 1.80-5.14, p < .001), were associated with higher risk of mortality. CONCLUSIONS: Older age (≥65 years old), male gender, hypertension, CVDs, diabetes, COPD and malignancies were associated with greater risk of death from COVID-19 infection. These findings could help clinicians to identify patients with poor prognosis at an early stage.

Liver injury is associated with severe coronavirus disease 2019 (COVID-19) infection: A systematic review and meta-analysis of retrospective studies.

The coronavirus disease 2019 (COVID-19) outbreak is a major threat to human beings. Lung injury has been reported as the major outcome of COVID-19 infection. However, liver damage has also been considered to occur in severe cases. The current meta-analysis of retrospective studies was carried out to summarize available findings on the association between liver injury and severity of COVID-19 infection. Online databases including PubMed, Scopus, Web of Science, and Cochrane Library were searched to detect relevant publications up to 1 April 2020, using relevant keywords. To pool data, a fixed- or random-effects model was used depending on the heterogeneity between studies. Furthermore, publication bias test and sensitivity analysis were also applied. In total, 20 retrospective studies with 3428 COVID-19 infected patients (severe cases, n = 1455; mild cases, n = 1973), were included in this meta-analysis. Higher serum levels of aspartate aminotransferase (weighted mean difference, 8.84 U/L; 95% confidence interval [CI] 5.97 to 11.71; P < 0.001), alanine aminotransferase (weighted mean difference, 7.35 U/L; 95% CI, 4.77 to 9.93; P < 0.001), total bilirubin (weighted mean difference, 2.30 mmol/L; 95% CI, 1.24 to 3.36; P < 0.001), and lower serum levels of albumin (weighted mean difference, -4.24 g/L; 95% CI, -6.20 to -2.28; P < 0.001) were associated with a significant increase in the severity of COVID-19 infection. The incidence of liver injury, as assessed by serum analysis (aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin levels), seems to be higher in patients with severe COVID-19 infection.

Genotype-related variations in proinflammatory and regulatory cytokine levels in treated and treatment-naive HCV-infected patients.

Hepatitis C virus (HCV) modulates immune-related inflammatory responses to induce milder reactions leading to virus persistence. In this regard, the present study aimed to investigate the link between the HCV genotypes and the proinflammatory and regulatory cytokine levels. Ninety patients with hepatitis C infection (68 treatment-naive and 22 treated patients) and 76 healthy blood donors were studied. The serum levels of IFN-γ, IL-10, IL-17A, and IL-21 were measured by ELISA in the patients and healthy controls. IL-10, IL-17A, and IL-21 levels were significantly higher in HCV patients than in the healthy controls. The same cytokines were also higher in genotype 3a-infected patients compared with genotype 1a-infected patients. Interestingly, in treated patients, lower serum levels of IL-17A and IL-21 were detected in G3a-infected individuals, but not in those infected with G1a. G3a viral load displayed a significant correlation with IL-21 and IL-17A levels. In addition, G1a viral load correlated with IL-10 levels. In G3a-infected patients, a significant association was found between IL-17A serum levels and ALT. We found differences in IL-21 and IL-17A serum levels among HCV-infected patients which were genotype dependent. Since Th17-associated cytokines are associated with the progression of liver disease in HCV patients, IL-17A and IL-21 can be used as important biological markers for evaluating the immunopathogenesis of chronic hepatitis. Our results suggest that HCV G3a along with immune responses such as cytokines in HCV patients should be taken into account when interpreting clinical data and IFN-based therapeutic response.

Determination of Helicobacter pylori virulence-associated genes in duodenal ulcer and gastric biopsies.

Background:Helicobacter pylori (H. pylori or Hp) has been strongly associated with the peptic ulcer diseases, chronic gastritis, ulcers, and gastric cancer. Genes associated with pathogenicity have been designated for H. pylori, and some of them appear to be related to more severe clinical consequences of the infection. The present study was conducted to determine cagA, vacA, cagE, iceA1, oipA, and iceA2 genes in H. pylori strains isolated from gastroduodenal patients, who referred to Shariati hospital in Tehran, Iran. Methods: Gastric biopsy specimens were collected during endoscopy from patients, who referred to the Shariati hospital in Tehran, Iran during January and November 2015. After isolation of H. pylori from the biopsy culture, genomic DNA was extracted and subsequently used to identify H. pylori and virulence genes using specific primers. Results: The isolation rate of H. pylori strains was 65.7% (169/257). The frequency of cagA, vacA, cagE, iceA1, oipA, and iceA2 was 143 (% 84.6), 169 (100%), 131 (77.5%), 97 (57.3%), 89 (52.6%), and 72 (42.6%), respectively. Conclusion: In this study, a significant difference was observed between investigated genes and strains isolated from PUD and GC patients (p<0.05).

Bacterial Persister Cells: Mechanisms of Formation, Control, and Eradication.

Bacterial Persister Cells (BPCs) are quiescent, slow-growing or growth-arrested phenotypic variants of normal bacterial cells that are transiently tolerant to antibiotics. It seems that persister cells are the main cause of the recurrence of various chronic infections. Stress response (RpoS-mediated), Toxin-Antitoxin (TA) systems, inhibition of ATP production, Reactive Oxygen Species (ROS), efflux pumps, bacterial SOS response, cell-to-cell communication and stringent response (ppGpp- mediated) are the primary potential mechanisms for persistence cell formation. However, eradicating persistent cells is challenging as the specific molecular mechanisms that initiate their formation remain fuzzy and unknown. Here we reviewed and summarized the current understanding of how bacterial persister cells are formed, controlled, and destroyed.

Clinical, epidemiological, laboratory, and radiological characteristics of novel Coronavirus (2019-nCoV) in retrospective studies: A systemic review and meta-analysis.

BACKGROUND: In December 2019, a novel pneumonia related to the 2019 coronavirus unexpectedly developed in Wuhan, China. We aimed to review data of the novel Coronavirus (2019-nCoV) by analyzing all the published retrospective studies on the clinical, epidemiological, laboratory, and radiological characteristics of patients with 2019-nCoV. METHODS: We searched in four bibliographic databases PubMed, Scopus, Embase, and Web of Science) for studies March 10, 2020 focused on the clinical, epidemiological, laboratory, and radiological characteristics of patients with 2019-nCoV for meta-analysis. The Newcastle-Ottawa Scale was used to quality assessment, and publication bias was analyzed by Egger's test. In the meta-analysis, a random-effects model with Stata/SE software, v.14.1 (StataCorp, College Station, TX) was used to obtain a pooled incidence rate. RESULTS: Fifty studies were included in this systematic review and meta-analysis with 8815 patients and the mean age was 46 years and 4647 (52.7%) were male. The pooled incidences rate of clinical symptoms were: fever (83%, 95% CI: 0.77, 0.89), cough (59%, 95% CI: 0.48, 0.69), myalgia or fatigue (31%, 95% CI: 0.23, 0.39), sputum production (29%, 95% CI: 0.21, 0.39), and dyspnea (19%, 95% CI: 0.12, 0.26). The pooled incidence rate of acute respiratory distress syndrome (ARDS) was (22%, 95% CI: 0.00, 0.60). CONCLUSION: The results of this systemic review and meta-analysis present a quantitative pooled incidence rate of different characters of 2019-nCoV and has great potential to develop diagnosis and patient's stratification in 2019-nCoV. However, this conclusions of this study still requisite to be warranted by more careful design, larger sample size multivariate studies to corroborate the results of this meta-analysis.

Development and biological assessment of MMAE-trastuzumab antibody-drug conjugates (ADCs).

BACKGROUND: Trastuzumab, a humanized monoclonal antibody targeting Human Epidermal growth factor Receptor 2 (HER2), is a therapeutic option used for the treatment of patients with HER2-overexpressing breast cancers. The primary purpose of the present study was to establish a trastuzumab-based antibody drug conjugate (ADC) to enhance the biopharmaceutical profile of trastuzumab. METHODS: In this study, trastuzumab was linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) through a peptide linker. Following conjugation, MMAE-trastuzumab ADCs were characterized using SDS-PAGE, UV/VIS, and cell-based ELISA. The inhibitory effects of the ADCs were measured on MDA-MB-453 (HER2-positive cells) and HEK-293 (HER2-negative cells) using in vitro cell cytotoxicity and colony formation assays. RESULTS: Our findings showed that approximately 3.4 MMAE payloads were conjugated to trastuzumab. MMAE-trastuzumab ADCs produced six bands, including H2L2, H2L, HL, H2, H, and L in non-reducing SDS-PAGE. The conjugates exhibited the same binding ability to MDA-MB-453 as unconjugated trastuzumab. The MTT assay showed a significant improvement in the trastuzumab activity following MMAE conjugation, representing a higher antitumor activity as compared with unconjugated trastuzumab. Furthermore, ADCs were capable of potentially inhibiting colony formation in HER2-positive cells, as compared with trastuzumab. CONCLUSION: MMAE-trastuzumab ADCs represent a promising therapeutic strategy to treat HER2-positive breast cancer.

Cardiac injury is associated with severe outcome and death in patients with Coronavirus disease 2019 (COVID-19) infection: A systematic review and meta-analysis of observational studies.

Coronavirus disease 2019 (COVID-19) is a global pandemic impacting 213 countries/territories and more than 5,934,936 patients worldwide. Cardiac injury has been reported to occur in severe and death cases. This meta-analysis was done to summarize available findings on the association between cardiac injury and severity of COVID-19 infection. Online databases including Scopus, PubMed, Web of Science, Cochrane Library and Google Scholar were searched to detect relevant publications up to 20 May 2020, using relevant keywords. To pool data, a fixed- or random-effects model was used depending on the heterogeneity between studies. In total, 22 studies with 3684 COVID-19 infected patients (severe cases=1095 and death cases=365) were included in this study. Higher serum levels of lactate dehydrogenase (weighted mean difference (WMD) =108.86 U/L, 95% confidence interval (CI)=75.93-141.79, p<0.001) and creatine kinase-MB (WMD=2.60 U/L, 95% CI=1.32-3.88, p<0.001) were associated with a significant increase in the severity of COVID-19 infection. Furthermore, higher serum levels of lactate dehydrogenase (WMD=213.44 U/L, 95% CI=129.97-296.92, p<0.001), cardiac troponin I (WMD=26.35 pg/mL, 95% CI=14.54-38.15, p<0.001), creatine kinase (WMD=48.10 U/L, 95% CI=0.27-95.94, p = 0.049) and myoglobin (WMD=159.77 ng/mL, 95% CI=99.54-220.01, p<0.001) were associated with a significant increase in the mortality of COVID-19 infection. Cardiac injury, as assessed by serum analysis (lactate dehydrogenase, cardiac troponin I, creatine kinase (-MB) and myoglobin), was associated with severe outcome and death from COVID-19 infection.

Chimeric Antigen Receptor Based Therapy as a Potential Approach in Autoimmune Diseases: How Close Are We to the Treatment?

Despite significant breakthroughs in understanding of immunological and physiological features of autoimmune diseases, there is currently no specific therapeutic option with prolonged remission. Cell-based therapy using engineered-T cells has attracted tremendous attention as a practical treatment for autoimmune diseases. Genetically modified-T cells armed with chimeric antigen receptors (CARs) attack autoreactive immune cells such as B cells or antibody-secreting plasma cells. CARs can further guide the effector and regulatory T cells (Tregs) to the autoimmune milieu to traffic, proliferate, and exert suppressive functions. The genetically modified-T cells with artificial receptors are a promising option to suppress autoimmune manifestation and autoinflammatory events. Interestingly, CAR-T cells are modified to a new chimeric auto-antibody receptor T (CAAR-T) cell. This cell, with its specific-antigen, recognizes and binds to the target autoantibodies expressing autoreactive cells and, subsequently, destroy them. Preclinical studies of CAR-T cells demonstrated satisfactory outcomes against autoimmune diseases. However, the lack of target autoantigens remains one of the pivotal problems in the field of CAR-T cells. CAR-based therapy has to pass several hurdles, including stability, durability, trafficking, safety, effectiveness, manufacturing, and persistence, to enter clinical use. The primary goal of this review was to shed light on CAR-T immunotherapy, CAAR-T cell therapy, and CAR-Treg cell therapy in patients with immune system diseases.

Investigating the sequential patterns of methamphetamine use initiation in Iran.

BACKGROUND: Methamphetamine (MA) remains one of the most commonly used amphetamine-type stimulants, accounting for the second most widely-used substance after marijuana. Due to increased use of MA, a wide variety of research has focused on the patterns of MA use initiation among adolescents. Nevertheless, there are few data available for people who use MA. The present study set out to assess the sequential patterns of substance use initiation in patients with MA use disorders in Iran. MATERIALS AND METHODS: This cross-sectional study described substance initiation patterns for 302 patients who used MA admitted to hospitals and psychiatric centers of Shiraz University of Medical Sciences. The study was conducted between April 2015 and June 2016. After obtaining informed consents, participants were interviewed by trained interviewers using face-to-face, semi-structured interviews. The collecting data were analyzed using the chi square tests and one-way analysis of variance (ANOVA) tests to compare the relationship between qualitative and quantitative variables, respectively. RESULTS: Out of 302 participants enrolled in the study, 16 (5.3%) and 286 (94.7%) were female and male, respectively. The mean age of participants in the study was 37.29 years. The mean age of onset of MA use was found to be 15.9 years. 46.1% of the patients started MA use before 15 years. 77.2% of the patients who used MA had family members with a history of substance use. 93.71% of the patients who used MA started substance use with tobacco, alcohol, or opium, as the most frequent substances. Tobacco, as the first substance or starting substance, exhibited the most widely-used substance (69.53% of the cases). Tobacco-alcohol-cannabis-opium-heroin-MA sequencing was significantly related to the early onset of the substance use. Early-onset substance use was significantly higher in those with lower income, primary education, and family history of substance use. No significant relationship was found between employment status with the age of onset of substance use, and different substance use with marital status. CONCLUSION: Tobacco, alcohol and opium can be considered as the main sequencing substances for initiation to MA use. Standardized measures to decrease and control access to main starting and sequencing substances, including tobacco, alcohol, and opium, can greatly help decrease the early onset of the MA use, develop suitable prevention, and establish early intervention strategies.

Protective effects of pharmacological agents against aminoglycoside-induced nephrotoxicity: A systematic review.

Introduction: Aminoglycosides have been long used for antibacterial treatment and are still commonly used in clinical practice. Despite their extensive application and positive effects, drug-related toxicity is considered as the main obstacle for aminoglycosides. Aminoglycosides induce nephrotoxicity through the endocytosis and accumulation of the antibiotics in the epithelial cells of proximal tubule. Most importantly, however, a number of pharmacological agents were demonstrated to have protective activities against nephrotoxicity in experimental animals.Areas covered: In the present systematic review, the authors provide and discuss the mechanisms and epidemiological features of aminoglycoside-induced nephrotoxicity, and focus mainly on recent discoveries and key features of pharmacological interventions. In total, 39 articles were included in this review.Expert opinion: The majority of studies investigated gentamicin-induced nephrotoxicity in animal models. Antioxidants, chemicals, synthetic drugs, hormones, vitamins, and minerals showed potential values to prevent gentamicin-induced nephrotoxicity. Indicators used to evaluate the effectiveness of nephroprotection included antioxidative indexes, inflammatory responses, and apoptotic markers. Among the nephroprotective agents studied, herbs and natural antioxidant agents showed excellent potential to provide a protective strategy against gentamicin-induced nephrotoxicity.

Greener synthesis of Rod Shaped Zinc Oxide Nanoparticles using Lilium ledebourii tuber and evaluation of their Leishmanicidal activity.

BACKGROUND: Nanoparticles (NPs) with unique chemical and physical properties can be used for therapeutic purposes because of their strong antimicrobial activates. Nanoparticles have been used as an antimicrobial agents to inhibit microbial growth. OBJECTIVES: In view of the strong antimicrobial activity of nanoparticles, the biogenic synthesis and leishmanicidal activity of rod-shaped zinc oxide (R-ZnO) nanoparticles was explored using Lilium ledebourii tuber extract. MATERIALS AND METHODS: The ensuing nanoparticles are characterized by UV-visible spectroscopy, X-ray diffraction and transmission electron microscopy and their leishmanicidal activity evaluated against the Leishmania major (L. major) by MTT assay. RESULTS: The R-ZnO nanoparticles displayed excellent leishmanicidal activity against the L. major as they significantly inhibited the amastigotes. The IC50 values of R-ZnO nanoparticles being ~ 0.001 mg.mL-1. R-ZnO nanoparticles can inhibit L. major growth in a dose-dependent manner under in vitro conditions. CONCLUSION: A simple, low-cost feasible and eco-friendly procedure was developed for biosynthesis of R-ZnO nanoparticles using natural bioresource that can inhibit human parasite cells growth in a dose-dependent manner under in vitro conditions.

Molecular Analysis of PBP1A in Streptococcus pneumoniae Isolated from Clinical and Normal Flora Samples in Tehran, Iran: A Multicenter Study.

The emergence of high-level penicillin resistance in pneumococcal isolates has seriously complicated the treatment of pneumococcal infections in recent years. The purpose of this study was to determine the serotype, antimicrobial susceptibility, molecular typing, and genetic analysis of the penicillin-binding protein 1a (pbp1a) gene in pneumococcal isolates with high-level resistance to penicillin in Tehran, Iran. PCR amplification, sequencing, and data analysis of the pbp1a gene were carried out for isolates with high-level resistance to penicillin. Antibiotic susceptibility tests showed that the multiple drug resistance pattern "E-CD-OX-TS-T" was the most prevalent (18.0%). The most common serotypes were serotypes 14 (21%), 19F (17%), 23F (16%), and 3 (16%). The highest mutation rates were found in STMK conserved motifs, but no mutation was detected in the other two sequence motifs (SRN and KTG). High-level resistant isolates showed mutations at residues TSQF (574-577) NTGY. Pneumococcal isolates have experienced shifts toward higher penicillin minimal inhibitory concentration levels and other ß-lactams. The results of this study show that the presence of multiple substitutions in the pbp1a gene in pneumococcal isolates is highly associated with a reduced affinity to penicillin.

Frequency of Mutations in Quinolone Resistance-Determining Regions and Plasmid-Mediated Quinolone Resistance in Shigella Isolates Recovered from Pediatric Patients in Tehran, Iran: An Overlooked Problem.

Fluoroquinolone (FQ) resistance in clinical isolates of Shigella species has been increasing reported in recent years. This study was carried out to find the mutations within the quinolone resistance-determining regions (QRDRs) and the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants among the clinical isolates of Shigella sp. in Tehran, Iran. A total of 50 Shigella isolates were collected from five teaching therapeutic centers in Tehran, Iran and analyzed for antibiotic susceptibility over a period of 20 months from July 2015 to January 2017. The PCR and direct nucleotide sequencing were used for genetic alterations in the QRDRs. The PMQR genes were detected using PCR. The results revealed four types of mutations in the QRDR of gyrA: 20 (40%) had a S83L mutation, 1 (2%) had a S83A mutation, 2 (4%) had a D87G mutation, and 1 (2%) isolate had a D87Y mutation. Mutations were also found at codon N57D, D200N, and E210K in three isolates. Seven hospitalized children had qnrS determinants, and one isolates had the mutation S83A, while two isolates had double mutations at S83L and/or D87G (Ser83Leu and Asp-87Gly). The PMQR gene-positive isolates had the single replacement of serine with leucine. In hospitalized children, two isolates had two types of PMQR determinants (qnrS and qnrA) and (qnrS and qnrB) at once. The results of this study indicate that the emergence of strains with mutations in the QRDR regions and the capture of PMQR determinants in strains may lead to failure in therapy with FQ and the widespread emergence of strains with high-level FQ resistance.