Treatment Of Gram-negative Bacterial Infections Research Articles

Protective Effects Of A Lipid Transfer Protein Isolated from Morinda citrifolia Seeds in Gentamicin-Induced Nephrotoxicity in Rats

Gentamicin is an aminoglycoside antibiotic used in the treatment of gram-negative bacterial infections. However, its prolonged use is limited due to a high risk of nephrotoxicity. This study aimed to investigate the protective effects of a lipid transfer protein isolated from Morinda citrifolia L., Rubiaceae, seeds against gentamicin-induced nephrotoxicity in rats, and in a proximal tubular epithelial cell line from Rhesus monkey (LLC-MK2). Treatment with 6.25–25 μg/ml of the protein protected cells against cytotoxicity induced by 2 mM gentamicin. In the in vivo study, protein treatment (8 mg/kg, orally administered daily for 7 days 2 h after intraperitoneal injection of 100 mg/kg gentamicin) improved the levels of creatinine, urea, and uric acid. Additionally, it alleviated oxidative stress and inflammation induced by gentamicin, including a reduction in myeloperoxidase activity and cytokine modulation. Data were corroborated with histological analysis showing attenuated alterations by protein treatment. These findings suggest that this protein protects against gentamicin-induced nephrotoxicity. In addition, this natural product may be as an adjunctive tool to reduce kidney toxicity and improve the clinical usage profile of gentamicin.

Berbamine Analogs Exhibit Differential Protective Effects From Aminoglycoside-Induced Hair Cell Death.

Hearing loss is the third most common chronic health condition in the United States and largely results from damage to sensory hair cells. Major causes of hair cell damage include aging, noise exposure, and medications such as aminoglycoside antibiotics. Due to their potent antibacterial properties and low cost, aminoglycosides are often used for the treatment of gram-negative bacterial infections, surpassing expensive antibiotics with fewer harmful side effects. However, their use is coupled with permanent hearing loss in over 20% of patients requiring these life-sustaining antibiotics. There are currently no FDA-approved drugs that prevent hearing loss from aminoglycosides. A previous study by our group identified the plant alkaloid berbamine as a strong protectant of zebrafish lateral line hair cells from aminoglycoside damage. This effect is likely due to a block of the mechanotransduction channel, thereby reducing aminoglycoside entry into hair cells. The present study builds on this previous work, investigating 16 synthetic berbamine analogs to determine the core structure underlying their protective mechanisms. We demonstrate that nearly all of these berbamine analogs robustly protect lateral line hair cells from ototoxic damage, with ED50 values nearing 20 nM for the most potent analogs. Of the 16 analogs tested, nine strongly protected hair cells from both neomycin and gentamicin damage, while one conferred strong protection only from gentamicin. These data are consistent with prior research demonstrating that different aminoglycosides activate somewhat distinct mechanisms of damage. Regardless of the mechanism, protection required the entire berbamine scaffold. Phenolic alkylation or acylation with lipophilic groups appeared to improve protection compared to berbamine, implying that these structures may be responsible for mitigating damage. While the majority of analogs confer protection by blocking aminoglycoside uptake, 18% of our analogs also confer protection via an uptake-independent mechanism; these analogs exhibited protection when delivered after aminoglycoside removal. Based on our studies, berbamine analogs represent a promising tool to further understand the pathology of aminoglycoside-induced hearing loss and can serve as lead compounds to develop otoprotective drugs.

Drugs for Gram-Negative Bugs From 2010-2019: A Decade in Review.

A literature review spanning January 1, 2010, to December 31, 2019, was conducted using the PubMed and ISI Web of Science databases to determine the breadth of publication activity in the area of gram-negative bacteria antimicrobial therapy. The number of articles was used as a reflection of scholarly activity. First, PubMed was searched using the following Medical Subject Headings (MeSH): antibacterial agents, Enterobacteriaceae, Acinetobacter, and Pseudomonas. A total of 12 643 articles were identified within PubMed, and 77 862 articles were identified within ISI Web of Science that included these terms. Second, these articles were categorized by antibiotic class to identify relative contributions to the literature by drug category. Third, these studies were used to identify key trends in the treatment of gram-negative bacterial infections from the past decade. This review highlights advances made in the past 10 years in antibacterial pharmacotherapy and some of the challenges that await the next decade of practice.

Increased Azithromycin Susceptibility of Multidrug-Resistant Gram-Negative Bacteria on RPMI-1640 Agar Assessed by Disk Diffusion Testing.

Increasing antibiotic resistances and a lack of new antibiotics render the treatment of Gram-negative bacterial infections increasingly difficult. Therefore, additional approaches are being investigated. Macrolides are not routinely used against Gram-negative bacteria due to lack of evidence of in vitro effectiveness. However, it has been shown that Pseudomonas spp. are susceptible to macrolides in liquid RPMI-1640 and clinical data suggest improvement in patients’ outcomes. So far, these findings have been hardly applicable to the clinical setting due to lack of routine low-complexity antimicrobial susceptibility testing (AST) for macrolides. We therefore optimized and compared broth microdilution and disk diffusion AST. Multidrug-resistant Gram-negative bacteria (Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa) were tested for azithromycin susceptibility by disk diffusion and broth microdilution in Mueller–Hinton and RPMI-1640 media. Azithromycin susceptibility of Enterobacteriaceae and a subgroup of P. aeruginosa increased significantly on RPMI-1640 agar compared to Mueller–Hinton agar. Further, a significant correlation (Kendall, τ, p) of zone diameters and minimal inhibitory concentrations (MICs) was found on RPMI-1640 agar for E. coli (−0.4279, 0.0051), E. cloacae (−0.3783, 0.0237) and P. aeruginosa (−0.6477, <0.0001). Performing routine disk diffusion AST on RPMI-1640 agar may lead to the identification of additional therapeutic possibilities for multidrug-resistant bacterial infections in the routine clinical diagnostic setting.

Emergence of Escherichia coli harbouring mcr-1 and mcr-3 genes in North West Algerian farmlands

ObjectivesColistin resistance has emerged worldwide, threatening the efficacy of colistin treatment of Gram-negative bacterial infections. Farms have been recognised as an important reservoir of genes conferring resistance to colistin. This study aimed to isolate and characterise colistin-resistant bacteria in farmlands located in the region of Oran, northwest Algeria. MethodsForty environmental samples were collected between May 2016 and March 2018 at eight agricultural sites in the Oran region. ResultsFrom the 40 samples, 103 colistin-resistant isolates were isolated from agricultural soil (n = 52), irrigation water (n = 31) and manure (n = 20). Eight isolates were identified as Escherichia coli, including six and two isolates carrying the mcr-1 and mcr-3 gene, respectively. All eight E. coli isolates were non-susceptible to amoxicillin, amoxicillin/clavulanic acid, ticarcillin, nalidixic acid, ciprofloxacin, gentamicin, trimethoprim/sulfamethoxazole and rifamycin; two were also non-susceptible to cefotaxime, cefepime and aztreonam and carried the blaTEM-12 gene in addition to mcr-1. The six mcr-1-carrying E. coli isolates (MIC ≥ 2 μg/mL) belonged to three sequences types, including ST10 (n = 3), ST405 (n = 2) and ST345 (n = 1), whereas the two mcr-3-carrying isolates were assigned to ST155. The conjugation assay was positive only for two mcr-1-positive isolates. ConclusionThese results show that farms are an important reservoir of colistin-resistant E. coli as well as other antimicrobial resistance genes such as ESBL genes. Transfer of manure from animals to soil and irrigation water might be disseminating a mix of multiple resistances, posing a worrying threat to human health.

Effect of fatty acids from ethanol extract of Moringa oleifera seeds on kidney function impairment and oxidative stress induced by gentamicin in rats

Gentamicin, an aminoglycoside drug, used for the treatment of Gram-negative bacterial infections. Despite its potency against bacterial infections, its clinical use is limited owing to nephrotoxicity effect. However, the study investigated the nephroprotective effect of fatty acids from ethanolic extract of Moringa oleifera seeds (EEMOS) against gentamicin-induced kidney injury in rats. Forty-five male Wistar rats, 100–160 g, were divided into 5 groups as follows: Group 1 (control), 5 rats, received 0.2 ml/100 g/day of propylene glycol orally for 28 days. Group 2, 10 rats, received 100 mg/kg/day (i.p) of gentamicin (GENT) for 8 days. Group 3–5, 10 rats each, treated with EEMOS orally for 28 days at graded doses of 100, 200 and 400 mg/kg respectively after GENT treatment. Twenty four after treatment, five rats from each group were sacrificed. The remaining 5 rats were sacrificed after 2 weeks recovery period from the drugs. The result showed that GENT elicited polyuria, elevated plasma creatinine, urea, and lower plasma electrolytes and creatinine clearance levels. Measurements of 24 h urinary output demonstrated marked decrease in creatinine and potassium levels in the GENT-treated group, whereas sodium level remain unchanged. Also, GENT caused significant decrease in superoxide dismutase and an increase in malondialdehyde levels in the kidney of the rats. Histopathological examination revealed evidence of necrosis of the kidney. Treatment with EEMOS significantly ameliorated the alterations caused by GENT in the plasma, urine and kidney homogenate of the rats. Hence, the mono- and poly-unsaturated fatty acids present in EEMOS were responsible for its renoprotective ability.

A Consolidated and Continuous Synthesis of Ciprofloxacin from a Vinylogous Cyclopropyl Amide.

Ciprofloxacin is a broad-spectrum antibiotic that is recognized as one of the World Health Organization's Essential Medicines. It is particularly effective in the treatment of Gram-negative bacterial infections associated with urinary, respiratory, and gastrointestinal tract infections. A streamlined and high yielding continuous synthesis of ciprofloxacin has been developed, which employs a chemoselective C-acylation step that precludes the need for intermediate isolations, extractions, or purifications. The end-to-end process has a residence time of 4.7 min with a 15.8 g/h throughput at laboratory scale and an overall isolated yield of 83%.

Pasireotide protects mammalian cochlear hair cells from gentamicin ototoxicity by activating the PI3K\u2013Akt pathway

Gentamicin is a widely used antibiotic for the treatment of gram-negative bacterial infections; however, its use often results in significant and permanent hearing loss. Hearing loss resulting from hair cell (HC) degeneration affects millions of people worldwide, and one major cause is the loss of sensory HCs in the inner ear due to aminoglycoside exposure. Strategies to overcome the apparently irreversible loss of HCs in mammals are crucial for hearing protection. Here, we report that the somatostatin analog pasireotide protects mouse cochlear HCs from gentamicin damage using a well-established in vitro gentamicin-induced HC loss model and that the otoprotective effects of pasireotide are due to Akt up-regulation via the PI3K–Akt signal pathway activation. We demonstrate active caspase signal in organ of Corti (OC) explants exposed to gentamicin and show that pasireotide treatment activates survival genes, reduces caspase signal, and increases HC survival. The neuropeptide somatostatin and its selective analogs have provided neuroprotection by activating five somatostatin receptor (SSTR1–SSTR5) subtypes. Pasireotide has a high affinity for SSTR2 and SSTR5, and the addition of SSTR2- and SSTR5-specific antagonists leads to a loss of protection. The otoprotective effects of pasireotide were also observed in a gentamicin-injured animal model. In vivo studies have shown that 13 days of subcutaneous pasireotide application prevents gentamicin-induced HC death and permanent hearing loss in mice. Auditory brainstem response analysis confirmed the protective effect of pasireotide, and we found a significant threshold shift at all measured frequencies (4, 8, 16, 24, and 32 kHz). Together, these findings indicate that pasireotide is a novel otoprotective peptide acting via the PI3K–Akt pathway and may be of therapeutic value for HC protection from ototoxic insults.

Deciphering the Role of Intramolecular Networking in Cholic Acid-Peptide Conjugates on the Lipopolysaccharide Surface in Combating Gram-Negative Bacterial Infections.

The presence of lipopolysaccharide and emergence of drug resistance make the treatment of Gram-negative bacterial infections highly challenging. Herein, we present the synthesis and antibacterial activities of cholic acid-peptide conjugates (CAPs), demonstrating that valine-glycine dipeptide-derived CAP 3 is the most effective antimicrobial. Molecular dynamics simulations and structural analysis revealed that a precise intramolecular network of CAP 3 is maintained in the form of evolving edges, suggesting intramolecular connectivity. Further, we found high conformational rigidity in CAP 3 that confers maximum perturbations in bacterial membranes relative to other small molecules. Interestingly, CAP 3-coated catheters did not allow the formation of biofilms in mice, and treatment of wound infections with CAP 3 was able to clear the bacterial infection. Our results demonstrate that molecular conformation and internal connectivity are critical parameters to describe the antimicrobial nature of compounds, and the analysis presented here may serve as a general principle for the design of future antimicrobials.

Selenium Nanoparticles Attenuate Gentamycin-Induced Nephrotoxicity and Hematotoxicity in Female Swiss Albino Mice

Gentamycin (GM) is a widely used antibiotic for the treatment of Gram-negative bacterial infections, but nephrotoxic effects limit its use. Selenium nanoparticles (SeNPs) have attracted worldwide research interest due to their high bioavailability and potential antioxidant property. This study was, therefore, designed to examine the protective effect of SeNPs on GM-induced changes in body and kidney weights, blood hematology, serum biochemistry parameters, and renal tissue markers of oxidative stress in female mice. GM was administered intraperitoneally (100 mg/kgb.w) and SeNPs were given by oral gavage (2 mg/kg b.w) for 10 consecutive days. GM treatment caused significant changes in the body and relative kidney weights and significant renal damage, evidenced by increased serum levels of urea, uric acid, creatinine, total proteins, and blood urea nitrogen (BUN), along with noteworthy histopathological alterations. A marked decrease in serum sodium and potassium ions, and kidney tissue antioxidative defense system (reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT)) was observed in GM-treated mice when compared with the normal mice. Furthermore, significant decrease in total white blood corpuscles (WBC) count, total platelets count (PLT), total red blood corpuscles (RBC) count, hemoglobin concentration (Hgb), and packed cell volume (PCV) was also revealed in GM-treated group. However, GM + SeNPs group had effectively reversed GM-induced alteration of both biochemical and renal histological structures. Our results suggested for the first time that SeNPs are potent antioxidant candidate against GM-induced oxidative kidney toxicity and hematoxicity in mice.

A novel framework to compare the effectiveness of β-lactamase inhibitors against extended-spectrum β-lactamase-producing Enterobacteriaceae

ObjectivesExtended-spectrum β-lactamases (ESBLs) present a serious challenge in the treatment of Gram-negative bacterial infections. ESBLs mediate resistance to most β-lactams, which may be reversed with the addition of an active β-lactamase inhibitor (such as tazobactam, relebactam and avibactam). However, various ESBLs may exhibit different susceptibilities to these inhibitors, which could impact efficacy. We proposed a framework for comparing the efficacy of these inhibitors when combined with the same β-lactam. MethodsThree clinical isolates of Klebsiella pneumoniae harbouring CTX-M-15 and one Escherichia coli isolate with SHV-12 were examined. Piperacillin MICs were determined by broth dilution using escalating concentrations of tazobactam, relebactam and avibactam. The resulting MICs were characterized as response to inhibitor concentrations using an inhibitory sigmoid Emax model. Using the best-fit parameter values, the model was conditioned with fluctuating inhibitor concentrations to simulate instantaneous MICi profiles for each isolate–inhibitor pair. Using a simulated exposure of 4 g piperacillin every 8 h, %fT > MICi was estimated for each piperacillin/inhibitor combination. A hollowfibre infection model was subsequently used to validate the predicted effectiveness of selected combinations. ResultsIn all scenarios, piperacillin MIC reductions were well characterized with increasing inhibitor concentrations. As predicted by %fT > MICi, combining piperacillin with avibactam (61.4%–73.6%) was found to be superior to tazobactam (13.5%–44.5%) for suppressing bacterial growth over time. ConclusionWe illustrated a practical approach to compare the performance of different inhibitors. This platform may be used clinically to identify the optimal pairing of various β-lactams and β-lactamase inhibitors for individual isolates producing ESBLs.

How to optimize antibiotic pharmacokinetic/pharmacodynamics for Gram-negative infections in critically ill patients.

Optimized antibiotic dosing regimens improve survival rates in critically ill patients. However, dose optimization is challenging because of fluctuating antibiotic pharmacokinetics both between patients and within a single patient. This study reviews the pharmacokinetic changes that occur in critically ill patients, along with the pharmacodynamics and toxicodynamics of antibiotics commonly used for the treatment of Gram-negative bacterial infections to formulate a recommendation for antibiotic dosing at the bedside. Recent studies highlight that critically ill patients do not achieve therapeutic antibiotic exposures with standard antibiotic dosing. Although dose increases are required, the method of administration, such as the use of β-lactam antibiotic continuous infusions and nebulized aminoglycoside administration, may improve efficacy and limit toxicity. In addition, the increased availability of therapeutic drug monitoring and antibiotic dosing software allow the formulation of individualized dosing regimens at the bedside. When prescribing antibiotic doses, the clinician should consider antibiotic pharmacokinetic and pharmacodynamic principles. Before initiating high-dose antibiotic therapy, therapeutic drug monitoring may be considered to assist the clinician to optimize antibiotic treatment and minimize potential toxicity.

Exploring the Pharmacokinetic/Pharmacodynamic Relationship of Relebactam (MK-7655) in Combination with Imipenem in a Hollow-Fiber Infection Model.

Resistance to antibiotics among bacterial pathogens is rapidly spreading, and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic/pharmacodynamic relationship of the novel β-lactamase inhibitor relebactam (REL; MK-7655) in a hollow-fiber infection model. REL is intended for use with the carbapenem β-lactam antibiotic imipenem for the treatment of Gram-negative bacterial infections. In this study, we used an in vitro hollow-fiber infection model to confirm the efficacy of human exposures associated with the phase 2 doses (imipenem at 500 mg plus REL at 125 or 250 mg administered intravenously every 6 h as a 30-min infusion) against imipenem-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae Dose fractionation experiments confirmed that the pharmacokinetic parameter that best correlated with REL activity is the area under the concentration-time curve, consistent with findings in a murine pharmacokinetic/pharmacodynamic model. Determination of the pharmacokinetic/pharmacodynamic relationship between β-lactam antibiotics and β-lactamase inhibitors is complex, as there is an interdependence between their respective exposure-response relationships. Here, we show that this interdependence could be captured by treating the MIC of imipenem as dynamic: it changes with time, and this change is directly related to REL levels. For the strains tested, the percentage of the dosing interval time that the concentration remains above the dynamic MIC for imipenem was maintained at the carbapenem target of 30 to 40%, required for maximum efficacy, for imipenem at 500 mg plus REL at 250 mg.

Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of Staphylococcus aureus towards Polymyxins.

ABSTRACTStaphylococcus aureus is intrinsically resistant to polymyxins (polymyxin B and colistin), an important class of cationic antimicrobial peptides used in treatment of Gram-negative bacterial infections. To understand the mechanisms underlying intrinsic polymyxin resistance in S. aureus, we screened the Nebraska Transposon Mutant Library established in S. aureus strain JE2 for increased susceptibility to polymyxin B. Nineteen mutants displayed at least 2-fold reductions in MIC, while the greatest reductions (8-fold) were observed for mutants with inactivation of either graS, graR, vraF, or vraG or the subunits of the ATP synthase (atpA, atpB, atpG, or atpH), which during respiration is the main source of energy. Inactivation of atpA also conferred hypersusceptibility to colistin and the aminoglycoside gentamicin, whereas susceptibilities to nisin, gallidermin, bacitracin, vancomycin, ciprofloxacin, linezolid, daptomycin, and oxacillin were unchanged. ATP synthase activity is known to be inhibited by oligomycin A, and the presence of this compound increased polymyxin B-mediated killing of S. aureus. Our results demonstrate that the ATP synthase contributes to intrinsic resistance of S. aureus towards polymyxins and that inhibition of the ATP synthase sensitizes S. aureus to this group of compounds. These findings show that by modulation of bacterial metabolism, new classes of antibiotics may show efficacy against pathogens towards which they were previously considered inapplicable. In light of the need for new treatment options for infections with serious pathogens like S. aureus, this approach may pave the way for novel applications of existing antibiotics.

Potentiation of Antibiotic Activity by a Novel Cationic Peptide: Potency and Spectrum of Activity of SPR741.

Novel approaches for the treatment of multidrug-resistant Gram-negative bacterial infections are urgently required. One approach is to potentiate the efficacy of existing antibiotics whose spectrum of activity is limited by the permeability barrier presented by the Gram-negative outer membrane. Cationic peptides derived from polymyxin B have been used to permeabilize the outer membrane, granting antibiotics that would otherwise be excluded access to their targets. We assessed the in vitro efficacies of combinations of SPR741 with conventional antibiotics against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii Of 35 antibiotics tested, the MICs of 8 of them were reduced 32- to 8,000-fold against E. coli and K. pneumoniae in the presence of SPR741. The eight antibiotics, azithromycin, clarithromycin, erythromycin, fusidic acid, mupirocin, retapamulin, rifampin, and telithromycin, had diverse targets and mechanisms of action. Against A. baumannii, similar potentiation was achieved with clarithromycin, erythromycin, fusidic acid, retapamulin, and rifampin. Susceptibility testing of the most effective antibiotic-SPR741 combinations was extended to 25 additional multidrug-resistant or clinical isolates of E. coli and K. pneumoniae and 17 additional A. baumannii isolates in order to rank the potentiated antibiotics. SPR741 was also able to potentiate antibiotics that are substrates of the AcrAB-TolC efflux pump in E. coli, effectively circumventing the contribution of this pump to intrinsic antibiotic resistance. These studies support the further development of SPR741 in combination with conventional antibiotics for the treatment of Gram-negative bacterial infections.

WCK 5222 (Cefepime-Zidebactam) Antimicrobial Activity against Clinical Isolates of Gram-Negative Bacteria Collected Worldwide in 2015.

WCK 5222 consists of cefepime combined with zidebactam, a bicyclo-acyl hydrazide β-lactam enhancer antibiotic with a dual action involving binding to Gram-negative bacterial PBP2 and β-lactamase inhibition. We evaluated the in vitro activity of cefepime-zidebactam against 7,876 contemporary (2015) clinical isolates of Enterobacteriaceae (n = 5,946), Pseudomonas aeruginosa (n = 1,291), and Acinetobacter spp. (n = 639) from the United States (n = 2,919), Europe (n = 3,004), the Asia-Pacific (n = 1,370), and Latin America (n = 583). The isolates were tested by a reference broth microdilution method for susceptibility against cefepime-zidebactam (1:1 and 2:1 ratios) and comparator agents. Cefepime-zidebactam was the most active compound tested against Enterobacteriaceae (MIC50/90, ≤0.03/0.12 μg/ml [1:1] and 0.06/0.25 μg/ml [2:1]; 99.9% of isolates were inhibited at ≤4 [1:1] and ≤8 μg/ml [2:1]). Cefepime-zidebactam was active against individual Enterobacteriaceae species (MIC50/90, ≤0.03 to 0.06/≤0.03 to 0.5 μg/ml [1:1]) and retained potent activity against carbapenem-resistant isolates (MIC50/90, 1/4 μg/ml; 99.3% of isolates were inhibited at ≤8 μg/ml [1:1]). Cefepime-zidebactam activity was consistent among geographic regions, and only one isolate showed MIC values of >8 μg/ml (1:1). Cefepime-zidebactam was also very active against P. aeruginosa with MIC50/90 values of 1/4 μg/ml, and 99.5% of isolates were inhibited at ≤8 μg/ml (1:1). The MIC values for cefepime-zidebactam at the 1:1 ratio were generally 2-fold lower than those for cefepime-zidebactam at the 2:1 ratio (MIC50/90, 2/8 μg/ml) and zidebactam alone (MIC50/90, 4/8 μg/ml). Against Acinetobacter spp., cefepime-zidebactam at 1:1 and 2:1 ratios (MIC50/90, 16/32 μg/ml for both) was 4-fold more active than cefepime or ceftazidime. Zidebactam exhibited potent in vitro antimicrobial activity against some organisms. These results support the clinical development of WCK 5222 for the treatment of Gram-negative bacterial infections, including those caused by multidrug-resistant isolates.

Cefiderocol. Inhibitor of penicillin-binding protein 3 (PBP3), Inhibitor of cell wall synthesis, Treatment of Gram-negative bacterial infections

Cefiderocol. Inhibitor of penicillin-binding protein 3 (PBP3), Inhibitor of cell wall synthesis, Treatment of Gram-negative bacterial infections

Protective effect of crocin on gentamicin-induced nephrotoxicity in rats.

Gentamicin is used for the treatment of Gram-negative bacterial infections. However, gentamicin administration is limited because of nephrotoxicity. The aim of the present study was to evaluate the protective effect of crocin against gentamicin-induced nephrotoxicity in rats. Thirty two male Wistar rats received gentamicin (100 mg/kg, IP), with or without crocin (100 mg/kg, IP) for seven consecutive days. Plasma creatinine and urea-nitrogen concentrations, oxidative stress and histopathological changes of kidney tissues were monitored. Administration of gentamicin resulted in significant increases in plasma creatinine and urea-nitrogen concentrations and renal tissue malondialdehyde (MDA) level, and a decrease in the renal tissue ferric reducing/antioxidant power (FRAP) level. Crocin decreased plasma creatinine and urea-nitrogen concentrations and tissue MDA level, but increased the level of tissue FRAP. In addition, gentamicin led to cellular damages including glomerular atrophy, cellular desquamation, tubular necrosis and fibrosis, epithelial oedema of proximal tubules, perivascular edema, vascular congestion and intra-tubular proteinaceous casts, all of which were partially recovered by crocin. Crocin has protective effects against functional disturbances, oxidative stress and tissue damages induced by gentamicin.

Investigational Agents for the Treatment of Gram-Negative Bacterial Infections: A Reality Check.

Antibiotic-resistant Gram-negative bacteria are, arguably, the most difficult organisms to treat, with a limited number of new antibiotics in the development pipeline. Currently 24 new agents in phase 1, phase 2, or phase 3 clinical development were identified for the potential treatment of infections caused by Gram-negative bacteria. Of these agents, most are improved iterations of known antibiotic classes, including new aminoglycosides, β-lactams, β-lactamase inhibitors, quinolones, and tetracyclines with greater potency or a broader spectrum of activity. However, novel structures also appear, with host defense peptide mimetics, boronic acid, and bridged diazabicyclooctane β-lactamase inhibitors and unique bacterial topoisomerase inhibitors. Most of the new agents have received a Qualified Infectious Disease Product (QIDP) designation that may help to accelerate FDA drug approvals. Because resistance will inevitably arise to any antibacterial agent, it will be necessary to continue to identify additional new agents in the future.

New antibiotics and antimicrobial combination therapy for the treatment of gram-negative bacterial infections.

Increasing rates of life-threatening infections due to multidrug-resistant (MDR) gram-negative bacteria, such as carbapenemase-producer strains, as well as pathogens that are resistant to all current therapeutic options, have been reported. The number of compounds that are currently being developed is still insufficient to control this global threat. We have reviewed the current available options for the treatment of MDR gram-negative infections, including combination regimens employing older antimicrobials and new compounds. A limited number of large trials have assessed the treatment options for commonly encountered resistant pathogens (e.g., Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa). Antimicrobials that were used in the past, such as colistin and fosfomycin, have been recently resumed and used in association with carbapenems, tigecycline, or aminoglycosides, showing a positive impact on clinical outcomes. New compounds belonging to various antimicrobial classes (e.g. beta-lactamase inhibitors, cephalosporins, glycyclines, aminoglycosides) have been investigated. Only few new molecules have an adequate activity against MDR gram-negative pathogens, especially carbapenemase-producer strains. Among these, ceftozolane/tazobactam has been recently approved for clinical use. Other compounds, such as avibactam combinations, plazomicin, and eravacycline, have shown promising activity in phase 2 and 3 clinical trials.