Drug Repositioning as a Therapeutic Strategy against Streptococcus pneumoniae: Cell Membrane as Potential Target.

A collection of repurposing drugs (Prestwick Chemical Library) containing 1200 compounds was screened to investigate the drugs' antimicrobial effects against planktonic cultures of the respiratory pathogen Streptococcus pneumoniae. After four discrimination rounds, a set of seven compounds was finally selected, namely (i) clofilium tosylate; (ii) vanoxerine; (iii) mitoxantrone dihydrochloride; (iv) amiodarone hydrochloride; (v) tamoxifen citrate; (vi) terfenadine; and (vii) clomiphene citrate (Z, E). These molecules arrested pneumococcal growth in a liquid medium and induced a decrease in bacterial viability between 90.0% and 99.9% at 25 µM concentration, with minimal inhibitory concentrations (MICs) also in the micromolar range. Moreover, all compounds but mitoxantrone caused a remarkable increase in the permeability of the bacterial membrane and share a common, minimal chemical structure consisting of an aliphatic amine linked to a phenyl moiety via a short carbon/oxygen linker. These results open new possibilities to tackle pneumococcal disease through drug repositioning and provide clues for the design of novel membrane-targeted antimicrobials with a related chemical structure.

Alnustone inhibits Streptococcus pneumoniae virulence by targeting pneumolysin and sortase A.

Streptococcus pneumoniae (S. pneumoniae) is a major Gram-positive opportunistic pathogen that causes pneumonia, bacteremia, and other fatal infections. This bacterium is responsible for more deaths than any other single pathogen in the world. Inexplicably, these symptoms persist despite the administration of effective antibiotics. Targeting pneumolysin (PLY) and sortase A (SrtA), the major virulence factors of S. pneumoniae, this study uncovered a novel resistance mechanism to S. pneumoniae infection. Using protein phenotype assays, we determined that the small molecule inhibitor alnustone is a potent drug that inhibits both PLY and SrtA. As essential virulence factors of S. pneumoniae, PLY and SrtA play a significant role in the occurrence of infection. Furthermore, evaluation using PLY-mediated hemolysis assay demonstrated alunstone had the potential to interrupt the haemolytic activity of PLY with treatment alunstone (4 µg/ml). Co-incubation of S. pneumoniae D39 SrtA with small-molecule inhibitors decreases cell wall-bound Nan A (pneumococcal-anchored surface protein SrtA), inhibits biofilm formation, and reduces biomass significantly. The protective effect of invasive pneumococcal disease (IPD) on murine S. pneumoniae was demonstrated further. Our study proposes a comprehensive bacteriostatic mechanism for S. pneumoniae and highlights the significant translational potential of targeting both PLY and SrtA to prevent pneumococcal infections. Our findings indicate that the antibacterial strategy of directly targeting PLY and SrtA with alnustone is a promising treatment option for S. pneumoniae and that alnustone is a potent inhibitor of PLY and SrtA.

ß-Lactam-Resistant Streptococcus pneumoniae Dynamics Following Treatment: A Dose-Response Meta-analysis.

BACKGROUND: Patient exposure to antibiotics promotes the emergence of drug-resistant pathogens. The aim of this study was to identify whether the temporal dynamics of resistance emergence at the individual-patient level were predictable for specific pathogen-drug classes. METHODS: Following a systematic review, a novel robust error meta-regression method for dose-response meta-analysis was used to estimate the odds ratio (OR) for carrying resistant bacteria during and following treatment compared to baseline. Probability density functions fitted to the resulting dose-response curves were then used to optimize the period during and/or after treatment when resistant pathogens were most likely to be identified. RESULTS: Studies of Streptococcus pneumoniae treatment with ß-lactam antibiotics demonstrated a peak in resistance prevalence among patients 4 days after completing treatment with a 3.32-fold increase in odds (95% confidence interval [CI], 1.71-6.46). Resistance waned more gradually than it emerged, returning to preexposure levels 1 month after treatment (OR, 0.98 [95% CI, .55-1.75]). Patient isolation during the peak dose-response period would be expected to reduce the risk that a transmitted pathogen is resistant equivalently to a 50% longer isolation window timed from the first day of treatment. CONCLUSIONS: Predictable temporal dynamics of resistance levels have implications both for surveillance and control.

Clinical and molecular characteristics of Streptococcus pneumoniae-associated hemophagocytic lymphohistiocytosis in children / 中华儿科杂志

Objective: To summarize the clinical features of Streptococcus pneumoniae-associated hemophagocytic syndrome (SP-HLH), and the serotypes and drug-resistant characteristics of the isolated strains. Methods: There were 15 children with SP-HLH admitted to the Pediatric Intensive Care Unit (PICU) of Beijing Children's Hospital, Capital Medical University from January 2013 to December 2020 were included in this study. Clinical data including children's general characteristics, clinical features, laboratory examinations, treatments, prognosis and the outcomes of follow-up by May 2021 were analyzed retrospectively. The serotypes and drug resistance of the isolated strains were identified. All children were divided into the clinical improvement group and the death group. Mann-Whitney U test, Fisher's exact test were used to compare the data of the two groups. Results: Among the 15 children with SP-HLH, 8 were males and 7 were females. The age of these children was 1.0 (1.0, 2.5) years. Regarding the primary infection, there were 9 cases of severe pneumonia, 3 cases of meningitis and 3 cases of blood stream infection. None of these children had received pneumoniae conjugate vaccine (PCV) and all of them were admitted to the PICU. Respiratory failure was observed in 10 patients, acute renal injury in 5, and hemolytic uremic syndrome in 3 patients. All children received glucocorticoids and high-dose intravenous immunogloblin (IVIG) in addition to anti-infective treatment. Eight of the children were cured while the other 7 died. The neutrophil count in the death group was lower than that in the clinical improvement group ((5.0 (1.7, 9.3) × 109 vs. 5.2 (3.4, 10.5) ×109/L, Z =-2.43, P<0.015), and the length of hospital stay and days of PICU stay in the death group were both shorter than those in the improvement group statistically (3 (1, 11) vs. 39 (34, 48) d, 2 (1, 4) vs. 19 (12, 31) d, Z=-3.25, -3.24, both P=0.001). Ten serotypes of Streptococcus pneumoniae were identified, including 4 strains of 19F, 3 of 19A, 1 of 23F, 1 of 15A and 1 of 14, among which 9 strains (9/10) were covered by PCV13. All strains were resistant to erythromycin yet sensitive to vancomycin and linezolid. Conclusions: SP-HLH is more common in children under the age of 3, with a high mortality rate. The death cases have lower neutrophil count and rapid disease progression. The comprehensive treatment is anti-infective combined with glucocorticoids and high-dose IVIG. The predominant serotypes are 19F and 19A and all isolated strains were susceptible to vancomycin and linezolid.

Antibiotics prescription for targeted therapy of pediatric invasive pneumococcal diseases in China: a multicenter retrospective study.

BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) is a major cause of bacterial meningitis, septicemia and pneumonia in children. Inappropriate choice of antibiotic can have important adverse consequences for both the individual and the community. Here, we focused on penicillin/cefotaxime non-susceptibility of S. pneumoniae and evaluated appropriateness of targeted antibiotic therapy for children with IPD (invasive pneumococcal diseases) in China. METHODS: A multicenter retrospective study was conducted in 14 hospitals from 13 provinces in China. Antibiotics prescription, clinical features and resistance patterns of IPD cases from January 2012 to December 2017 were collected. Appropriateness of targeted antibiotics therapy was assessed. RESULTS: 806 IPD cases were collected. The non-susceptibility rates of S. pneumoniae to penicillin and cefotaxime were 40.9% and 20.7% respectively in 492 non-meningitis cases, whereas those were 73.2% and 43.0% respectively in 314 meningitis cases. Carbapenems were used in 21.3% of non-meningitis cases and 42.0% of meningitis cases for targeted therapy. For 390 non-meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were used in 17.9% and 8.7% of cases respectively for targeted therapy. For 179 meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were prescribed in 55.3% and 15.6% of cases respectively. Overall, inappropriate targeted therapies were identified in 361 (44.8%) of 806 IPD cases, including 232 (28.8%) cases with inappropriate use of carbapenems, 169 (21.0%) cases with inappropriate use of vancomycin and 62 (7.7%) cases with inappropriate use of linezolid. CONCLUSIONS: Antibiotic regimens for IPD definite therapy were often excessive with extensive prescription of carbapenems, vancomycin or linezolid in China. Antimicrobial stewardship programs should be implemented to improve antimicrobial use.

Is Multidrug Resistance in Acute Otitis Media with Streptococcus pneumoniae Associated with a More Severe Disease?

OBJECTIVES: Streptococcus pneumoniae is the leading bacterial etiologic agent in acute otitis media (AOM), and it produces a more severe inflammatory response than other otopathogens. Additionally, the presence of multidrug-resistant (MDR) S. pneumoniae is an important issue in the management of AOM. The present pilot study aimed to ascertain whether MDR S. pneumoniae is associated with a higher inflammatory response and/or a more severe disease. METHODS: This was a prospective, single-center study on nonpneumococcal conjugate vaccine-immunized pediatric patients with severe AOM. Demographic and clinical characteristics were recorded. Middle ear fluid was obtained and cultured for each patient; antibiotic-resistance profiling was tested for S. pneumoniae isolates. The C-reactive protein (CRP) level and complete blood count were determined. Patients with positive middle ear fluid culture for S. pneumoniae were divided into 2 groups according to antibiotic resistance profile: MDR and non-MDR. RESULTS: MDR S. pneumoniae was identified in 15 (35.7%) of the 42 eligible patients. Children in this group had significantly higher CRP levels (72.23 ± 62.92 vs. 14.96 ± 15.57 mg/L, p < 0.001), higher absolute neutrophil count (8.46 ± 3.97 vs. 5.22 ± 4.5 × 103/mm3, p = 0.004), higher percentage of neutrophils (52.85 ± 13.49% vs. 38.34 ± 16.16%, p = 0.004), and were more prone to develop acute mastoiditis (p = 0.01). Receiver operating characteristic analysis identified CRP as the best biomarker to discriminate between the 2 groups of patients (AUC = 0.891). CONCLUSION: MDR S. pneumoniae was associated with a more severe inflammatory response and a higher incidence of mastoiditis.

Pharmacokinetic/pharmacodynamic evaluation of the antimicrobial therapy of pneumococcal invasive disease in adults in post-PCV13 vaccine period in Madrid, Spain.

The objective of our study was to evaluate by pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the antimicrobials used for the treatment of invasive pneumococcal disease (IPD) in adults, including meningitis, are adequate considering the susceptibility profile of S. pneumoniae in Spain after the implantation of PVC13 vaccine. Pharmacokinetic parameters of benzylpenicillin and cefotaxime were obtained from the literature, and susceptibility data of invasive S. pneumoniae strains recovered in 2017 (post-PCV13 vaccination period) were provided by the Public Health Regional Laboratory of Madrid. We have also studied levofloxacin because it is used to treat pneumococcal pneumonia previously to be diagnosed as bacteremic pneumonia. Monte Carlo simulation was used to estimate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). All doses of benzylpenicillin except 2 mU q6h provide a high probability of treatment success for MIC values ≤ 1 mg/L; 4 mU q4h is even useful for MIC values up to 4 mg/L. This high dose, used for the treatment of meningitis, also provides high probability of treatment success for MIC ≤ 0.5 mg/L. At the susceptibility EUCAST breakpoint (≤ 0.5 mg/L), cefotaxime provides a high rate of PD target achievement, even at the lowest dose (1 g q8h). For meningitis, 2 g q6h ensures probabilities of target attainment ≥90% for MIC up to 1 mg/L. Our study confirms that after the implementation of PCV13 vaccine, the treatment with benzylpenicillin and cefotaxime provides high probability of the therapy success of IPD, including meningitis.

Traditional Japanese Herbal Medicine Hochu-Ekki-to Promotes Pneumococcal Colonization Clearance via Macrophage Activation and Interleukin 17A Production in Mice.

Streptococcus pneumoniae may colonize the nasopharynx, and as pneumococcal colonization causes invasive diseases and the subsequent transmission, reducing bacterial burden in the nasal cavity is critical. Hochu-ekki-to (TJ-41) is a traditional Japanese herbal medicine that exerts immunomodulatory effects in host cells. In this study, we investigated the potency of TJ-41 in modulating pneumococcal colonization clearance by activating host immunity. Mice, intranasally inoculated with pneumococci, were treated orally with TJ-41. During colonization, TJ-41 treatment significantly reduced pneumococcal burden and increased macrophage population in the nasopharynx. Furthermore, interleukin 17A production was significantly enhanced after TJ-41 treatment. In vitro experiment using nasal-derived cells revealed that pneumococcal antigen exposure upregulated the transcription of interleukin 17A in the TJ-41-treated group compared with that in the control group. Macrophages activated by killed bacteria were significantly increased in the presence of TJ-41 in an interleukin 17A-dependent manner. Moreover, TJ-41 enhanced phagocytosis, inhibited bacterial growth, and improved the antigen-presenting capacity of macrophages. Our results demonstrate that TJ-41 accelerates the clearance of pneumococcal nasopharyngeal colonization via macrophage activation. Subsequent production of interleukin 17A provides an additional benefit to effector cells.

Therapeutic Activity of Type 3 Streptococcus pneumoniae Capsule Degrading Enzyme Pn3Pase.

PURPOSE: Streptococcus pneumoniae (Spn) serotype 3 (Spn3) is considered one of the most virulent serotypes with resistance to conventional vaccine and treatment regimens. Pn3Pase is a glycoside hydrolase that we have previously shown to be highly effective in degrading the capsular polysaccharide of type 3 Spn, sensitizing it to host immune clearance. To begin assessing the value and safety of this enzyme for future clinical studies, we investigated the effects of high doses of Pn3Pase on host cells and immune system. METHODS: We assessed the enzyme's catalytic activity following administration in mice, and performed septic infection models to determine if prior administration of the enzyme inhibited repeat treatments of Spn3-challenged mice. We assessed immune populations in mouse tissues following administration of the enzyme, and tested Pn3Pase toxicity on other mammalian cell types in vitro. RESULTS: Repeated administration of the enzyme in vivo does not prevent efficacy of the enzyme in promoting bacterial clearance following bacterial challenge, with insignificant antibody response generated against the enzyme. Immune homeostasis is maintained following high-dose treatment with Pn3Pase, and no cytotoxic effects were observed against mammalian cells. CONCLUSIONS: These data indicate that Pn3Pase has potential as a therapy against Spn3. Further development as a drug product could overcome a great hurdle of pneumococcal infections.

Streptococcus pneumoniae metal homeostasis alters cellular metabolism.

Streptococcus pneumoniae colonizes the human nasopharyngeal mucosa and is a leading cause of community-acquired pneumonia, acute otitis media, and bacterial meningitis. Metal ion homeostasis is vital to the survival of this pathogen across diverse biological sites and contributes significantly to colonization and invasive disease. Microarray and qRT-PCR analysis revealed an upregulation of an uncharacterized operon (SP1433-1438) in pneumococci subjected to metal-chelation by N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN). Supplementation of zinc, cobalt, and nickel following TPEN treatment significantly abrogated induction. BLASTP comparisons and protein topology analysis predicted this locus to encode components of ATP binding cassette (ABC) transporters involved in multidrug resistance (SP1434-1435) and energy-coupling factor (ECF) transporters (SP1436-1438). Inductively coupled plasma mass spectrometry (ICP-MS) analysis identified differences in intracellular metal content in a Δ1434-8 mutant strain compared to parental T4R. Further, analysis of the secreted metabolome of WT and Δ1434-8 strains identified significant changes in pneumococcal glycolytic and amino acid metabolic pathways, indicating a shift towards mixed acid fermentation. Additionally, proteomic analysis revealed differentially expressed proteins in the Δ1434-8 mutant strain, with nearly 20% regulated by the global catabolite repressor, CcpA. Based on these findings, we propose that the transporters encoded by SP1433-1438 are involved in regulating the central metabolism of S. pneumoniae and contributing to bacterial survival during metal stress.

Inhibitory Effect of the Traditional Chinese Medicine Ephedra sinica granules on Streptococcus pneumoniae Pneumolysin.

Streptococcus pneumoniae (S. pneumoniae) is an opportunistic pathogen that causes pneumonia, meningitis and bacteremia in humans and animals. Pneumolysin (PLY), a major pore-forming toxin that is important for S. pneumoniae pathogenicity, is a promising target for the development of anti-infective agents. Ephedra sinica granules (ESG) is one of the oldest medical preparation with multiple biological activities (such as a divergent wind and cold effect); however, the detailed mechanism remains unknown. In this study, we found that ESG treatment significantly inhibited the oligomerization of PLY and then reduced the activity of PLY without affecting S. pneumoniae growth and PLY production. In a PLY and A549 cell co-incubation system, the addition of ESG resulted in significant protection against PLY-mediated cell injury. Furthermore, S. pneumoniae-infected mice showed decreased mortality, and alleviated tissue damage and inflammatory reactions following treatment with ESG. Our results indicate that ESG is a potential candidate treatment for S. pneumoniae infection that targets PLY. This finding partially elucidates the mechanism of the Chinese herbal formula ESG in the treatment of pneumococcal disease.

Herbal Drug EPs 7630 versus Amoxicillin in Patients with Uncomplicated Acute Bacterial Rhinosinusitis: A Randomized, Open-Label Study.

OBJECTIVE: Previous investigations suggest the use of extract from the root of Pelargonium sidoides (EPs 7630) for the therapy of uncomplicated acute upper airway inflammations, due to its strong antimicrobial and immunomodulatory effect. We aimed to compare clinical efficacy, safety and bactericidal effect of EPs 7630 and amoxicillin monotherapy in treatment of patients with mild to moderate acute bacterial rhinosinusitis (ABRS). METHODS: Fifty ABRS patients were divided into two groups by randomization. Group 1 (n = 25) received EPs 7630 tablets, 3 × 20 mg/day per os for 10 days. Group 2 (n = 25) received amoxicillin tablets 3 × 500 mg/day per os, for 10 days. We assessed total symptom score (TSS), individual symptom scores for each symptom (nasal obstruction, rhinorrhea, postnasal drip, facial pain/pressure, loss of the sense of smell), endoscopic findings, including total endoscopic score (TES) and individual endoscopic signs (mucosal edema, mucopurulent secretion), before and after treatment. Samples of discharge taken from the middle meatus of all patients were cultivated for bacteria before and after therapy. RESULTS: Higher absolute improvement after treatment was found for TSS, nasal obstruction, facial pain/pressure, impaired sense of smell, TES, mucosal edema and mucopurulent secretion in EPs 7630 group compared to amoxicillin group (P < .001 for all parameters). However, there were no differences in absolute improvement of rhinorrhea score and postnasal drip score between groups (P = .248; P = .679, respectively). Fewer types of bacteria grew on culture from middle meatal samples in EPs 7630 group compared to amoxicillin group. There were no reported adverse events from patients from either group. CONCLUSION: Our results demonstrated better clinical and antimicrobial efficacy of EPs 7630 than amoxicillin. EPs 7630 was shown as a potent agent and good alternative to antibiotic treatment of uncomplicated ABRS.

Ceftaroline for severe community-acquired pneumonia: A real-world two-centre experience in Italy and Spain.

BACKGROUND: Ceftaroline is one of latest additions to the armamentarium for treating community-acquired pneumonia (CAP). This study aimed to describe the outcome of severe CAP (SCAP) in a cohort of hospitalised patients treated with ceftaroline. METHODS: A retrospective, observational study of patients with SCAP treated with ceftaroline in two hospitals in Spain and Italy. The primary objective was to explore 30-day mortality after diagnosis of SCAP. RESULTS: During the study period the following were observed: there were 89 cases of SCAP treated with ceftaroline and 53 cases used in combination with other antibiotics (60%). Overall, 30-day mortality and clinical failure were 20% (18 of 89) and 36% (32 of 89), respectively. Independent predictors of 30-day mortality were: increasing age (OR for 1 year increase 1.0, 95% CI 1.0-1.1, P 0.043), presence of solid neoplasm (OR 4.0, 95% CI 1.0-15.1, P 0.044) and concomitant therapy with oseltamivir (OR 8.5, 95% CI 1.2°57.3, P 0.029). The only independent predictor of clinical failure was the time elapsing from SCAP diagnosis to ceftaroline therapy (OR for each passing day 1.5, 95% CI 1.1-1.9, P 0.003). The clinical success rate was 64% (57 of 89). In the subgroups of patients with proven Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) infection, clinical success was 83% (10 of 12), 75% (three of four) and 56% (five of nine), respectively. CONCLUSIONS: Considering its spectrum of activity, ceftaroline could represent an important therapeutic option for SCAP. Further studies are needed to identify the precise clinical success rate against MRSA in a larger cohort of patients with SCAP.

C-Reactive Protein-Based Strategy to Reduce Antibiotic Dosing for the Treatment of Pneumococcal Infection.

C-reactive protein (CRP) is a component of innate immunity. The concentration of CRP in serum increases in microbial infections including Streptococcus pneumoniae infection. Employing a mouse model of pneumococcal infection, it has been shown that passively administered human wild-type CRP protects mice against infection, provided that CRP is injected into mice within two hours of administering pneumococci. Engineered CRP (E-CRP) molecules have been reported recently; unlike wild-type CRP, passively administered E-CRP protected mice against infection even when E-CRP was injected into mice after twelve hours of administering pneumococci. The current study was aimed at comparing the protective capacity of E-CRP with that of an antibiotic clarithromycin. We established a mouse model of pneumococcal infection in which both E-CRP and clarithromycin, when used alone, provided minimal but equal protection against infection. In this model, the combination of E-CRP and clarithromycin drastically reduced bacteremia and increased survival of mice when compared to the protective effects of either E-CRP or clarithromycin alone. E-CRP was more effective in reducing bacteremia in mice treated with clarithromycin than in untreated mice. Also, there was 90% reduction in antibiotic dosing by including E-CRP in the antibiotic-treatment for maximal protection of infected mice. These findings provide an example of cooperation between the innate immune system and molecules that prevent multiplication of bacteria, and that should be exploited to develop novel combination therapies for infections against multidrug-resistant pneumococci. The reduction in antibiotic dosing by including E-CRP in the combination therapy might also resolve the problem of developing antibiotic resistance.

Therapeutic effects of an orally administered edible seaweed-derived polysaccharide preparation, ascophyllan HS, on a Streptococcus pneumoniae infection mouse model.

Ascophyllan HS is a commercially available preparation of the edible brown alga Ascophyllum nodosum containing ascophyllan, a sulfated polysaccharide with diverse beneficial biological activities. In this study, the effects of ascophyllan HS were evaluated in a severe intranasal Streptococcus pneumoniae infection mouse model. The control untreated mice started to die on day 7 and 80% had died by day 14 post-infection. Continuous oral administration of ascophyllan HS before and after bacterial infection resulted in a remarkable increase in survival rate, with 90% of the low (167 mg/kg body weight/day) and 100% of the high (500 mg/kg body weight/day) dose ascophyllan HS-treated mice surviving at day 14 post-infection. Histopathological observation of the lungs of the infected mice revealed the induction of typical pneumonia features in the alveolar spaces of the untreated control mice, such as extensive infiltration of inflammatory cells, edema, and fibrin deposition. In contrast, notable levels of lung injuries or alterations were not observed in the ascophyllan HS-treated mice, and only a minor lesion was observed in one mouse. Furthermore, bacterial burdens in the lungs were significantly reduced in the ascophyllan HS-treated mice as compared to the control mice at day 4 post-infection. Significantly higher levels of IL-12 were detected in the serum of ascophyllan HS-treated mice than that of control mice measured at the end of the infection experiment (day 14). These results suggest that orally administered ascophyllan HS exerts a therapeutic effect on S. pneumoniae infection by activating the host defense systems. This is the first report of the therapeutic effect of an orally administered seaweed polysaccharide preparation on S. pneumoniae infection. Our findings suggest that ascophyllan HS has the potential to be developed as nutraceuticals and pharmaceuticals applicable for humans as well as a safe and promising therapeutic agent against S. pneumoniae infection.

Polyurethane-biomacromolecule combined foam dressing containing asiaticoside: fabrication, characterization and clinical efficacy for traumatic dermal wound treatment.

Polyurethane combined (PUC) foam dressings with various biomacromolecules were fabricated with the adsorption of asiaticoside and silver nanoparticles for traumatic wound treatment. Biomacromolecules had varying effects on physicochemical and mechanical properties of PU foam. With 2% incorporation, starches, high molecular weight chitosan and gelatin provided stiffer and more porous foams while carboxymethylcellulose had the highest compression strength but the lowest water vapor transmission. High water absorption was from foams with carboxymethylcellulose, alginate, hydroxypropyl methylcellulose and low molecular weight chitosan. Increasing the concentrations up to 12% had more prominent effect. However, powdery surface was noticed with poorer tensile properties that 6% incorporation was selected. FTIR spectra and DSC thermograms suggested interaction of PU formulation with biomacromolecules. EDS analysis confirmed existence of active compounds while acceptable stability was from sterilized PUC foam with alginate. On healthy volunteers, this selected foam dressing caused no skin irritation and retained moisture comparable to commercial product. In patients with traumatic dermal wounds, healing improvement with shorter wound closure time, higher reepithelialization and less pain score were from the selected foam dressing compared to standard gauze soaked with chlorhexidine. This PU-alginate combined foam dressing adsorbed with asiaticoside and silver nanoparticles proved advantages for traumatic dermal wound management.

Asymptomatic pharyngeal carriage rate of Streptococcus pyogenes, its associated factors and antibiotic susceptibility pattern among school children in Hawassa town, southern Ethiopia.

OBJECTIVES: The aim of this study was to determine the asymptomatic pharyngeal carriage rate of S. pyogenes, antimicrobial pattern and related risk factors among school children in Hawassa, southern Ethiopia. RESULTS: Out of 287 school children's screened, 35 (12.2%) were colonized with S. pyogenes. The carriage rate was significantly associated with factors such as sex (female p = 0.013) occupational status of mother (p = 0.002), lower income source (500-900 ETB, 1000-1500 ETB) (p = 0.001, and p = 0.042), history of hospitalization (p = 0.00) and residence of the children (p = 0.002). High level resistant to tetracycline and low level to vancomycin were observed, while penicillin, amoxicillin, erythromycin, chloramphenicol, and ceftriaxone were found to be effective.

Dietary zinc and the control of Streptococcus pneumoniae infection.

Human zinc deficiency increases susceptibility to bacterial infection. Although zinc supplementation therapies can reduce the impact of disease, the molecular basis for protection remains unclear. Streptococcus pneumoniae is a major cause of bacterial pneumonia, which is prevalent in regions of zinc deficiency. We report that dietary zinc levels dictate the outcome of S. pneumoniae infection in a murine model. Dietary zinc restriction impacts murine tissue zinc levels with distribution post-infection altered, and S. pneumoniae virulence and infection enhanced. Although the activation and infiltration of murine phagocytic cells was not affected by zinc restriction, their efficacy of bacterial control was compromised. S. pneumoniae was shown to be highly sensitive to zinc intoxication, with this process impaired in zinc restricted mice and isolated phagocytic cells. Collectively, these data show how dietary zinc deficiency increases sensitivity to S. pneumoniae infection while revealing a role for zinc as a component of host antimicrobial defences.

Pneumococcal susceptibility to antibiotics in carriage: a 17 year time series analysis of the adaptive evolution of non-vaccine emerging serotypes to a new selective pressure environment.

BACKGROUND: Pneumococcal conjugate vaccine (PCV) implementations led to major changes in serotype distribution and antibiotic resistance in carriage, accompanied by changes in antibiotic consumption. OBJECTIVES: To assess the dynamic patterns of antimicrobial non-susceptibility across non-PCV13 serotypes following PCV implementations. METHODS: We conducted a quasi-experimental interrupted time series analysis based on a 17 year French nationwide prospective cohort. From 2001 to 2018, 121 paediatricians obtained nasopharyngeal swabs from children with acute otitis media who were aged 6 months to 2 years. The main outcome was the rate of penicillin-non-susceptible pneumococci (PNSP), analysed by segmented regression. RESULTS: We enrolled 10 204 children. After PCV13 implementation, the PNSP rate decreased (-0.5% per month; 95% CI -0.9 to -0.1), then, after 2014, the rate slightly increased (+0.7% per month; 95% CI +0.2 to +1.2). Global antibiotic use within the previous 3 months decreased over the study period (-22.2%; 95% CI -33.0 to -11.3), but aminopenicillin use remained high. Among the main non-PCV13 serotypes, four dynamic patterns of penicillin susceptibility evolution were observed, including unexpected patterns of serotypes emerging while remaining or even becoming penicillin susceptible. In contrast to PNSP strains, for these latter patterns, the rate of co-colonization with Haemophilus influenzae increased concomitant with their emergence. CONCLUSIONS: In a context of continuing high antibiotic selective pressure, a progressive increase in PNSP rate was observed after 2014. However, we highlighted an unexpected variability in dynamic patterns of penicillin susceptibility among emerging non-PCV13 serotypes. Antibiotic resistance may not be the only adaptive mechanism to antimicrobial selective pressure, and co-colonization with H. influenzae may be involved.

Colonization rate of Streptococcus pneumoniae, its associated factors and antimicrobial susceptibility pattern among children attending kindergarten school in Hawassa, southern Ethiopia.

OBJECTIVE: The aim of this study was to determine the colonization rate of Streptococcus pneumoniae, antimicrobial susceptibility pattern and associated risk factors among children attending kindergarten school in Hawassa, Ethiopia. RESULTS: Out of 317 study participants, 68 (21.5%) were colonized with S. pneumoniae. Colonization rate was significantly associated with factors such as age (3 to 4 years old) (P = 0.01), having a sibling whose age was less than 5 years (P = 0.011), sharing a bed with parents (P = 0.005), cooking within bedroom (P = 0.002), and previous hospitalization (P = 0.004). Forty-four (64.6%), 33 (48.5%), and 2942.6%) of S. pneumoniae isolated were resistant to cotrimoxazole, penicillin, and tetracycline respectively.