Antibiotics

Stenotrophomonas maltophilia is a multidrug-resistant bacterium that is difficult to treat in hospitals worldwide, leading to high mortality. Published data describing the use of monotherapy or combination therapy and which one is better is still unclear. We aimed to investigate the efficacy of monotherapy and combination therapy in the treatment of S. maltophilia infections. We performed a systematic review of combination therapy and additionally a systematic review and meta-analysis to determine the effects of monotherapy versus combination therapy on mortality in S. maltophilia infections. Electronic databases: Cochrane Library, PubMed, Embase, ClinicalTrials.gov, Scopus, and OpenGrey were accessed. Of the 5030 articles identified, 17 studies were included for a systematic review of combination therapy, of which 4 cohort studies were finally included for meta-analysis. We found there is a trend of favorable outcomes with respect to mortality in the use of combination therapy to treat complex or severe S. maltopholia infections. A meta-analysis of monotherapy showed a statistical significance in the decreasing rate of mortality in hospital-acquired pneumonia (hazard ratio 1.42; 95% confidence interval, 1.04–1.94) compared to combination therapy, but not significant in bacteremia (hazard ratio 0.76; 95% confidence interval, 0.18–3.18). Further studies should continue to explore this association. Full article

Previous studies indicated that the use of a phage cocktail, composed of bacteriophages vB_SenM-2 and vB_Sen-TO17, is effective in killing cells of Salmonella enterica serovars Typhimurium and Enteritidis in vitro and in the Galleria mellonella animal model as efficiently as antibiotics (enrofloxacin or colistin) and induced fewer deleterious changes in immune responses. Here, we investigated the effects of this phage cocktail on the hematological parameters and selected biochemical markers in chickens infected with S. enterica serovar Typhimurium, in comparison to those caused by enrofloxacin or colistin. We found that treatment with antibiotics (especially with enrofloxacin) caused nonbeneficial effects on red blood cell parameters, including hematocrit, MCV, MCH, and MCHC. However, Salmonella-induced changes in the aforementioned parameters were normalized by the use of the phage cocktail. Importantly, hepatotoxicity was suggested to be induced by both antibiotics on the basis of increased alanine transaminase (ALT) and aspartate aminotransferase (AST) activities, in contrast to the phage cocktail, which did not influence these enzymes. We conclude that phage therapy with the cocktail of vB_SenM-2 and vB_Sen-TO17 in Salmonella-infected chickens is not only as effective as antibiotics but also significantly safer for the birds than enrofloxacin and colistin. Full article

Background: In the case of intra-abdominal infections (IAI) in beta-lactam (BL) allergic patients, empiric antimicrobial therapy without BL is recommended; however, data regarding the outcome with alternative regimens are scarce. This study aimed to compare the outcomes of BL allergic (BLA) patients with IAI to those who were non-BLA (NBLA). Method: We conducted a case–control study in a French teaching hospital, between 1 January 2016 and 31 August 2021. BLA patients with IAI treated with fluoroquinolone or aztreonam and metronidazole were matched with controls treated with BL, on age, sex, disease severity, IAI localization, and healthcare-associated infection (HAI) status. We compared rates of therapeutic failures, adverse events, and HAI, and then assessed factors associated with therapeutic failure using a logistic regression model. Results: The therapeutic failure rate was 14% (p > 0.99) in both groups of 43 patients, and there was no significant difference in the adverse events rate (p > 0.99) and HAI rate (p = 0.154). Factors independently associated with therapeutic failure were higher BMI (OR 1.16; 95%CI [1.00–1.36]; p = 0.041), longer hospital length of stay (OR 1,20; 95%CI [1.08–1.41]; p = 0.006), and inadequate empiric antimicrobial therapy (OR 11.71; 95%CI [1.43–132.46]; p = 0.025). Conclusion: The outcomes of BLA patients with IAI treated without BL were the same as those for NBLA patients treated with BL. Full article

Tuberculosis is a highly contagious disease caused by the Mycobacterium tuberculosis complex (MTBC). Although TB is treatable, multidrug-resistant, extensively drug-resistant, and totally drug-resistant forms of M. tuberculosis have become a new life-threatening concern. New anti-TB drugs that are capable of curing these drug-resistant strains are urgently needed. The purpose of this study is to determine the antimycobacterial activity of D-enantiomer human lactoferricin 1-11 (D-hLF 1-11) against mycobacteria in vitro using a 3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyltetrazolium bromide colorimetric assay, resazurin microplate assay, and microscopic observation drug susceptibility assay. Three previously described antimicrobial peptides, protegrin-1, AK 15-6, and melittin, with potent anti-TB activity, were included in this study. The findings suggest that D-hLF 1-11 can inhibit the growth of M. tuberculosis with a minimum inhibitory concentration of 100–200 µg/mL in susceptible, isoniazid (INH)-monoresistant, rifampicin (RF)-monoresistant, and MDR strains. The peptide can also inhibit some nontuberculous mycobacteria and other MTBC in similar concentrations. The antibiofilm activity of D-hLF 1-11 against the biofilm-forming M. abscessus was determined by crystal violet staining, and no significant difference is observed between the treated and untreated biofilm control. The checkerboard assay was subsequently carried out with M. tuberculosis H37Rv and the results indicate that D-hLF 1-11 displays an additive effect when combined with INH and a synergistic effect when combined with RF, with fractional inhibitory concentration indices of 0.730 and 0.312, respectively. The red blood cell hemolytic assay was initially applied for the toxicity determination of D-hLF 1-11, and negligible hemolysis (<1%) was observed, despite a concentration of up to 4 mg/mL being evaluated. Overall, D-hLF 1-11 has potential as a novel antimycobacterial agent for the future treatment of drug-sensitive and drug-resistant M. tuberculosis infections. Full article

This study aimed to determine the immunity, survival rate, and disease resistance of Litopenaeus vannamei treated using quercetin and florfenicol alone or in combination, after infection with acute hepatopancreatic necrosis syndrome caused by Vibrio parahaemolyticus (VP_AHPND). After infection with VP_AHPND, different types of feed were given to the shrimp for 5 days, including a control diet (drug-free), florfenicol only diet (15 mg/kg), quercetin only diet (400 mg/kg), a low-dose florfenicol/quercetin combined diet (200 mg/kg quercetin + 7.0 mg/kg florfenicol), a moderate-dose florfenicol/quercetin combined diet (400 mg/kg quercetin + 15 mg/kg florfenicol), and a high-dose florfenicol/quercetin combined diet (800 mg/kg quercetin + 30 mg/kg florfenicol). The cumulative mortality of shrimp was significantly reduced in the drug combination groups compared with either drug used alone (p < 0.05). The density of Vibrio was significantly lower and the immune parameters were significantly increased in the drug combination groups compared with either drug used alone (p < 0.05). Moreover, in the drug combination groups, the hepatopancreas tubules showed better integrity and structure compared with those when either drug was used alone. Therefore, compared with single drug treatment, the florfenicol and quercetin combination enhanced disease resistance, survival, and immune activity of VP_AHPND-infected shrimp. When the combination treatment is used, the dosage of florfenicol can be reduced and a better therapeutic effect is obtained. Full article

With the development of sequencing technology and further scientific research, an increasing number of biosynthetic gene clusters associated with secondary Streptomyces metabolites have been identified and characterized. The encoded genes of a family of regulators designated as PAS-LuxR are gradually being discovered in some biosynthetic gene clusters of polyene macrolide, aminoglycoside, and amino acid analogues. PAS-LuxR family regulators affect secondary Streptomyces metabolites by interacting with other family regulators to regulate the transcription of the target genes in the gene cluster. This paper provides a review of the structure, function, regulatory mechanism, and application of these regulators to provide more information on the regulation of secondary metabolite biosynthesis in Streptomyces, and promote the application of PAS-LuxR family regulators in industrial breeding and other directions. Full article

Background. Aeromonas necrotizing fasciitis (NF) causes high rates of amputation and mortality, even after aggressive surgical debridement and antibacterial therapy. This study investigated the effects of rational use of antibiotics and education by infectious disease (ID) physicians on Aeromonas NF treatment outcomes. Methods. Retrospective review for conducted for four years (period I, without an ID physician, December 2001 to December 2005) and 15 years (period II, with an ID physician, January 2006 to March 2021). In period II, the hospital-wide computerized antimicrobial approval system (HCAAS) was also implemented. A pretest-posttest time series analysis compared the two periods. Differences in clinical outcomes, demographics, comorbidities, signs and symptoms, laboratory findings, Aeromonas antibiotic susceptibility, and antibiotic regimens were compared between the two periods. Results. There were 19 patients in period I and 53 patients in period II. Patients had a lower rate of amputation or mortality in period II (35.8%) compared with period I (63.2%). Forty-four patients (61.1%) had polymicrobial infections. In the emergency room, the rate of misdiagnosis decreased from 47.4% in period I to 28.3% in period II, while effective empiric antibiotic usage increased from 21.1% in period I to 66.0% in period II. After the ID physician’s adjustment, 69.4% received monotherapy in period II compared to 33.3% in period I. Conclusions. Because Aeromonas NF had a high mortality rate and was often polymicrobial, choosing an antibiotic regimen was difficult. Using the HCAAS by an experienced ID physician can improve rational antibiotic usage and clinical outcomes in Aeromonas NF. Full article

Resistance to colistin generated by the mcr-1 gene in Enterobacteriaceae is of great concern due to its efficient worldwide spread. Despite the fact that the Lima region has a third of the Peruvian population and more than half of the national pig and poultry production, there are no reports of the occurrence of the mcr-1 gene in Escherichia coli isolated from livestock. In the present work, we studied the occurrence of E. coli carrying the mcr-1 gene in chicken and pig farms in Lima between 2019 and 2020 and described the genomic context of the mcr-1 gene. We collected fecal samples from 15 farms in 4 provinces of Lima including the capital Lima Metropolitana and recovered 341 E. coli isolates. We found that 21.3% (42/197) and 12.5% (18/144) of the chicken and pig strains were mcr-1-positive by PCR, respectively. The whole genome sequencing of 14 mcr-1-positive isolates revealed diverse sequence types (e.g., ST48 and ST602) and the presence of other 38 genes that confer resistance to 10 different classes of antibiotics, including beta-lactamase bla_CTX-M-55. The mcr-1 gene was located on diverse plasmids belonging to the IncI2 and IncHI1A:IncHI1B replicon types. A comparative analysis of the plasmids showed that they contained the mcr-1 gene within varied structures (mikB–mcr1–pap2, ISApl1–mcr1–pap2, and Tn6330). To the best of our knowledge, this is the first attempt to study the prevalence of the mcr-1 gene in livestock in Peru, revealing its high occurrence in pig and chicken farms. The genetic diversity of mcr-1-positive strains suggests a complex local epidemiology calling for a coordinated surveillance under the One-Health approach that includes animals, retail meat, farmers, hospitals and the environment to effectively detect and limit the spread of colistin-resistant bacteria. Full article

Biphasic calcium phosphate (BCP) serves as one of the substitutes for bone as it consists of an intimate mixture of beta-tricalcium phosphate (β-TCP) and hydroxyapatite (HAP) in different ratios. BCP, because of its inbuilt properties such as osteoconductivity, biocompatibility, and biostability in several clinical models serves as a bone substituent for orthopedic applications. Therefore, the present study aimed to assess the effectiveness of silver (Ag) nanoparticles (NPs) combined with BCP composites for the orthopedic sector of bone tissue regeneration and growth. In this regard, we first synthesized Ag-BCP microclusters by the double-emulsion method and then characterized the composite for various physicochemical properties, including the crystallinity and crystal structure, bonding and functionality, porosity, morphology, surface charges, topography, and thermal stability. In addition, the antibacterial activity of Ag-BCP was tested against gram-positive and gram-negative microorganisms such as Staphylococcus aureus, Candida albicans, and Escherichia coli. Finally, the cytocompatibility of Ag-BCP was confirmed against the fibroblast cells in vitro. Full article

Clinically, fungal pneumonia rarely occurs in adults, and invasive fungal infections can cause substantial morbidity, and mortality due to sepsis and septic shock. In the present study, we have designed peptides that exhibit potent antifungal activities against fluconazole-resistant Candida albicans in physiological monovalent, and divalent ionic buffers, with minimal fungicidal concentrations ranging from 16 to 32 µM. None of these tested peptides resulted in the development of drug resistance similar to fluconazole. Among them, the PS1-2 peptide did not induce stimulation of macrophages by C. albicans, and it exerted antifungal and anti-inflammatory effects against C. albicans-induced intratracheal infection, in an acute lung injury mouse model. PS1-2 is likely a novel therapeutic agent for the control, and prevention of drug-resistant C. albicans infection, and our findings may be useful for designing antimicrobial peptides to combat fungal infection. Full article

Antibiotic resistance is a serious global threat, and the misuse of antibiotics is considered its main cause. It is characterized by the expression of bacterial defense mechanisms, e.g., β-lactamases, expulsion pumps, and biofilm development. Acinetobacter baumannii and Pseudomonas aeruginosa are antibiotic-resistant species that cause high morbidity and mortality. Several alternatives are proposed to defeat antibiotic resistance, including antimicrobial peptides, bacteriophages, and plant compounds. Terpenes from different plant essential oils have proven antimicrobial action against pathogenic bacteria, and evidence is being generated about their effect against antibiotic-resistant species. That is the case for oregano essential oil (Lippia graveolens), whose antibacterial effect is widely attributed to carvacrol, its main component; however, minor constituents could have an important contribution. The analyzed evidence reveals that most antibacterial evaluations have been performed on single species; however, it is necessary to analyze their activity against multispecies systems. Hence, another alternative is using plant compounds to inactivate hydrolytic enzymes and biofilms to potentiate antibiotics’ effects. Despite the promising results of plant terpenes, more extensive and deep mechanistic studies are needed involving antibiotic-resistant multispecies to understand their full potential against this problem. Full article

Antimicrobial stewardship programs (ASPs) are a central component in reducing the overprescription of unnecessary antibiotics, with multiple studies showing benefits in the reduction of bacterial resistance. Less commonly, ASPs have been performed in outpatient settings, but there is a lack of available data in these settings. We implemented an ASP in a large regional outpatient setting to assess its feasibility and effectiveness. Over a 5-year post-implementation period, compared to the pre-intervention period, a significant reduction in antibiotic prescription occurred, with a reduction in resistance in E. coli urinary isolates. ASP activities also were found to be cost-effective, with a reduction in medication prescription. Full article

Staphylococcus epidermidis is a major nosocomial pathogen that frequently forms biofilms on indwelling medical devices. This study aimed to investigate the synergistic antimicrobial and antibiofilm activities of octyl gallate (OG) in combination with penicillin and bacitracin against S. epidermidis. Antimicrobial synergy was assessed by conducting checkerboard titration assays, and antibiofilm activity was determined with biofilm assays and fluorescence microscopy analysis. The presence of 8 µg/mL of OG increased both the bacteriostatic and bactericidal activities of penicillin and bacitracin against S. epidermidis. It lowered the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of penicillin by eight-fold and those of bacitracin by four-fold. Moreover, when used with penicillin or bacitracin, OG significantly decreased the level of biofilm production by preventing microcolony formation. Furthermore, OG significantly permeabilized the bacterial cell wall, which may explain its antimicrobial synergy with penicillin and bacitracin. Together, these results demonstrate that OG, a food-grade antioxidant, can be potentially used as a drug potentiator to enhance the antimicrobial and antibiofilm activities of penicillin and bacitracin against S. epidermidis. Full article

Whole genome sequencing (WGS) is a powerful tool to analyze bacterial genomes rapidly, and can be useful to study and detect AMR genes. We carried out WGS on a group of Escherichia coli (n = 30), sampled from healthy animals and farm environment in four pigsties in northern Italy. Two × 250bp paired end sequencing strategy on Illumina MiSeq™ was used. We performed in silico characterization of E. coli isolates through the web tools provided by the Center for Genomic Epidemiology (cge.cbs.dtu.dk/services/) to study AMR and virulence genes. Bacterial strains were further analyzed to detect phenotypic antimicrobial susceptibility against several antimicrobials. Data obtained from WGS were compared to phenotypic results. All 30 strains were MDR, and they were positive for the genes bla_CTX-M and bla_TEM as verified by PCR. We observed a good concordance between phenotypic and genomic results. Different AMR determinants were identified (e.g., qnrS, sul, tet). Potential pathogenicity of these strains was also assessed, and virulence genes were detected (e.g., etsC, gad, hlyF, iroN, iss), mostly related to extraintestinal E. coli pathotypes (UPEC/APEC). However, enterotoxin genes, such as astA, ltcA and stb were also identified, indicating a possible hybrid pathogenic nature. Various replicons associated to plasmids, previously recovered in pathogenic bacteria, were identified (e.g., IncN and IncR plasmid), supporting the hypothesis that our strains were pathogenic. Eventually, through WGS it was possible to confirm the phenotypic antibiotic resistance results and to appreciate the virulence side of our ESBL-producing E. coli. These findings highlight the need to monitor commensal E. coli sampled from healthy pigs considering a One Health perspective. Full article

Excessive antimicrobial use contributes to the development of antimicrobial resistance. In the Eastern Mediterranean region (EMR), there is dearth of information on the prevalence of antimicrobial use in patients hospitalized in acute healthcare settings, clinical indications, types of antimicrobials prescribed, and quality indicators for prescriptions. Between September and December 2019, seven countries in the EMR conducted a standardized point prevalence survey. All patients present in the hospital wards at 8 a.m. on the day of the survey constituted the sample population. We collected data, including patient characteristics, antimicrobials received, therapeutic indication according to predefined lists, and markers of prescribing quality. The survey included data from 139 hospitals in seven countries. Among the 19,611 inpatients surveyed, 11,168 patients received at least one antimicrobial {crude prevalence: 56.9% (95%CI: 56.2–57.6%). The top three classes of antimicrobials prescribed were third-generation cephalosporins (26.7%), beta-lactam penicillins (18.1%), and imidazole derivatives (n = 1655, 9.8%). Carbapenems were most frequently prescribed for the treatment of healthcare-associated infections. Compliance with quality indicators of antimicrobial use was limited where treatment guidelines were available for 41% of antimicrobial prescriptions and targeted antimicrobial treatment represented 21% of therapeutic indications. Overall hospital antimicrobial use was high in countries of the EMR, pointing to the need to design and implement context-specific antimicrobial stewardship programs to optimize antimicrobial use and reduce antimicrobial resistance. Full article

Cell-penetrating peptides (CPPs) are natural or engineered peptide sequences with the intrinsic ability to internalize into a diversity of cell types and simultaneously transport hydrophilic molecules and nanomaterials, of which the cellular uptake is often limited. In addition to this primordial activity of cell penetration without membrane disruption, multivalent antimicrobial activity accompanies some CPPs. Antimicrobial peptides (AMPs) with cell-penetrability exert their effect intracellularly, and they are of great interest. CPPs with antimicrobial activity (CPAPs) comprise a particular class of bioactive peptides that arise as promising agents against difficult-to-treat intracellular infections. This short review aims to present the antibacterial, antiparasitic, and antiviral effects of various cell-penetrating antimicrobial peptides currently documented. Examples include the antimicrobial effects of different CPAPs against bacteria that can propagate intracellularly, like Staphylococcus sp., Streptococcus sp., Chlamydia trachomatis, Escherichia coli, Mycobacterium sp., Listeria sp., Salmonella sp. among others. CPAPs with antiviral effects that interfere with the intracellular replication of HIV, hepatitis B, HPV, and herpes virus. Additionally, CPAPs with activity against protozoa of the genera Leishmania, Trypanosoma, and Plasmodium, the etiological agents of Leishmaniasis, Chagas’ Disease, and Malaria, respectively. The information provided in this review emphasizes the potential of multivalent CPAPs, with anti-infective properties for application against various intracellular infections. So far, CPAPs bear a promise of druggability for the translational medical use of CPPs alone or in combination with chemotherapeutics. Moreover, CPAPs could be an exciting alternative for pharmaceutical design and treating intracellular infectious diseases. Full article

Fungal infections are often consequent to prolonged antibiotic treatments. Vancomycin (Van) is the first-choice antibiotic in the treatment of Staphylococcus aureus infections associated with colonization of catheter surfaces. We demonstrate the direct effect of Van in promoting the formation of the biofilm of the emergent yeast pathogen Candida auris, developed in the conventional polystyrene microwell plate model, as well as on silicone surfaces (22 and 28% increase in total biomass, respectively) and on an S. aures biofilm, residual after vancomycin treatment, where C. auris achieved 99% of the mixed biofilm population. The effect of Van was assessed also in vivo, in the Galleria mellonella infection model, which showed higher mortality when infected with the yeast pathogen in the presence of the antibiotic. This evidence enhances awareness of the potential risk associated with prolonged antibiotic use in promoting fungal infections. Full article

It is urgent to find new antibiotic classes against multidrug-resistant bacteria as the rate of discovery of new classes of antibiotics has been very slow in the last 50 years. Recently, pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic-heterocycle have been identified as a new broad-spectrum antibiotic class with activity against Gram-negative bacteria. The active imine moiety of the reported lead pyrrolobenzodiazepine compounds was replaced with amide to obtain the non-DNA binding and noncytotoxic dilactam analogues to understand the structure-activity relationship further and improve the safety potential of this class. The synthesised compounds were tested against panels of multidrug-resistant Gram-positive and Gram-negative bacteria, including WHO priority pathogens. Minimum inhibitory concentrations for the dilactam analogues ranged from 4 to 32 mg/L for MDR Gram-positive bacteria, compared to 0.03 to 2 mg/L for the corresponding imine analogues. At the same time, they were found to be inactive against MDR Gram-negative bacteria, with a MIC > 32 mg/L, compared to a MIC of 0.5 to 32 mg/L for imine analogues. A molecular modelling study suggests that the lack of imine functionality also affects the interaction of PBDs with DNA gyrase. This study suggests that the presence of N10-C11 imine moiety is crucial for the broad-spectrum activity of pyrrolobenzodiazepines. Full article