Treatment Of Gram-negative Infections Research Articles

Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria.

Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors a Zn2+ ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two N-formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn2+ ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in Enterobacteriaceae as well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.

Relationship Between Real-time TDM-guided Pharmacodynamic Target Attainment of Continuous Infusion Beta-lactam Monotherapy and Microbiologic Outcome in the Treatment of Critically Ill Children With Severe Documented Gram-negative Infections.

To explore the relationship between real-time therapeutic drug monitoring (TDM)-guided pharmacodynamic target attainment of continuous infusion (CI) beta-lactam monotherapy and microbiological outcome in the treatment of critically ill children with severe documented Gram-negative infections. Observational, monocentric, retrospective study of critically ill patients receiving CI piperacillin-tazobactam, ceftazidime, or meropenem in monotherapy for documented Gram-negative infections optimized by means of a real-time TDM-guided strategy. Average steady-state beta-lactam concentrations (Css) were calculated for each patient, and the beta-lactam Css/minimum inhibitory concentration (MIC) ratio was selected as a pharmacodynamic parameter of efficacy. The Css/MIC ratio was defined as optimal if ≥4, quasi-optimal if between 1 and 4, and suboptimal if <1. The relationship between Css/MIC and microbiological outcome was assessed. Forty-six TDM assessments were carried out in 21 patients [median age 2 (interquartile range: 1-8) years]. Css/MIC ratios were optimal in 76.2% of cases. Patients with optimal Css/MIC ratios had both a significantly higher microbiological eradication rate (75.0% vs. 0.0%; P = 0.006) and lower resistance development rate (25.0% vs. 80.0%; P = 0.047) than those with quasi-optimal or suboptimal Css/MIC ratios. Quasi-optimal/suboptimal Css/MIC ratio occurred more frequently when patients had infections caused by pathogens with MIC values above the European Committee on Antimicrobial Susceptibility Testing clinical breakpoint (100.0% vs. 6.3%; P < 0.001). Real-time TDM-guided pharmacodynamic target attainment of CI beta-lactam monotherapy allowed to maximize treatment efficacy in most critically ill children with severe Gram-negative infections. Attaining early optimal Css/MIC ratios of CI beta-lactams could be a key determinant associated with microbiological eradication during the treatment of Gram-negative infections. Larger prospective studies are warranted for confirming our findings.

EPH10 Carbapenem-Resistant Gram-Negative Pathogens in Brazil: Analysis from Patients in a Laboratory Network

Treatment of gram-negative infections has become increasingly complicated by the emergence of carbapenem-resistant (CR) Enterobacterales, Pseudomonas aeruginosa (Pa) and Acinetobacter baumannii. Despite their clinical and economic impact, there is a lack of robust national data in Brazil. Our objective was to determine the frequency of Enterobacterales and Pa in Brazil from 2018-2020.

Evaluating the Efficacy of Eravacycline and Omadacycline against Extensively Drug-Resistant Acinetobacter baumannii Patient Isolates

For decades, the spread of multidrug-resistant (MDR) Acinetobacter baumannii has been rampant in critically ill, hospitalized patients. Traditional antibiotic therapies against this pathogen have been failing, leading to rising concerns over management options for patients. Two new antibiotics, eravacycline and omadacycline, were introduced to the market and have shown promising results in the treatment of Gram-negative infections. Since these drugs are newly available, there is limited in vitro data about their effectiveness against MDR A. baumannii or even susceptible strains. Here, we examined the effectiveness of 22 standard-of-care antibiotics, eravacycline, and omadacycline against susceptible and extensively drug-resistant (XDR) A. baumannii patient isolates from Cooper University Hospital. Furthermore, we examined selected combinations of eravacycline or omadacycline with other antibiotics against an XDR strain. We demonstrated that this collection of strains is largely resistant to monotherapies of carbapenems, fluoroquinolones, folate pathway antagonists, cephalosporins, and most tetracyclines. While clinical breakpoint data are not available for eravacycline or omadacycline, based on minimum inhibitory concentrations, eravacycline was highly effective against these strains. The aminoglycoside amikacin alone and in combination with eravacycline or omadacycline yielded the most promising results. Our comprehensive characterization offers direction in the treatment of this deadly infection in hospitalized patients.

Causes of polymyxin treatment failure and new derivatives to fill the gap.

Polymyxins are a class of antibiotics that were discovered in 1947 from programs searching for compounds effective in the treatment of Gram-negative infections. Produced by the Gram-positive bacterium Paenibacillus polymyxa and composed of a cyclic peptide chain with a peptide-fatty acyl tail, polymyxins exert bactericidal effects through membrane disruption. Currently, polymyxin B and colistin (polymyxin E) have been developed for clinical use, where they are reserved as "last-line" therapies for multidrug-resistant (MDR) infections. Unfortunately, the incidences of strains resistant to polymyxins have been increasing globally, and polymyxin heteroresistance has been gaining appreciation as an important clinical challenge. These phenomena, along with bacterial tolerance to this antibiotic class, constitute important contributors to polymyxin treatment failure. Here, we review polymyxins and their mechanism of action, summarize the current understanding of how polymyxin treatment fails, and discuss how the next generation of polymyxins holds promise to invigorate this antibiotic class.

Cost-Effectiveness of Imipenem/Cilastatin/Relebactam Compared with Colistin in Treatment of Gram-Negative Infections Caused by Carbapenem-Non-Susceptible Organisms.

IntroductionImipenem/cilastatin/relebactam (IMI/REL), a combination β-lactam antibiotic (imipenem) with a novel β-lactamase inhibitor (relebactam), is an efficacious and well-tolerated option for the treatment of hospitalized patients with gram-negative (GN) bacterial infections caused by carbapenem-non-susceptible (CNS) pathogens. This study examines cost-effectiveness of IMI/REL vs. colistin plus imipenem (CMS + IMI) for the treatment of infection(s) caused by confirmed CNS pathogens.MethodsWe developed an economic model comprised of a decision-tree depicting initial hospitalization, and a Markov model projecting long-term health and economic impacts following discharge. The decision tree, informed by clinical data from RESTORE-IMI 1 trial, modeled clinical outcomes (mortality, cure rate, and adverse events including nephrotoxicity) in the two comparison scenarios of IMI/REL versus CMS + IMI for patients with CNS GN infection. Subsequently, a Markov model translated these hospitalization stage outcomes (i.e., death or uncured infection) to long-term consequences such as quality-adjusted life years (QALYs). Sensitivity analyses were conducted to test the model robustness.ResultsIMI/REL compared to CMS + IMI demonstrated a higher cure rate (79.0% vs. 52.0%), lower mortality (15.2% vs. 39.0%), and reduced nephrotoxicity (14.6% vs. 56.4%). On average a patient treated with IMI/REL vs. CMS + IMI gained additional 3.7 QALYs over a lifetime. Higher drug acquisition costs for IMI/REL were offset by shorter hospital length of stay and lower AE-related costs, which result in net savings of $11,015 per patient. Sensitivity analyses suggested that IMI/REL has a high likelihood (greater than 95%) of being cost-effective at a US willingness-to-pay threshold of $100,000–150,000 per QALY.ConclusionsFor patients with confirmed CNS GN infection, IMI/REL could yield favorable clinical outcomes and may be cost-saving—as the higher IMI/REL drug acquisition cost is offset by reduced nephrotoxicity-related cost—for the US payer compared to CMS + IMI.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00607-x.

In vitro activity of imipenem/releactam and comparator agents against clinical bacterial isolates from patients with cancer

Gram-negative bacilli (GNB) are currently the predominant bacterial pathogens in patients with cancer. Many GNB have become problematic due to the widespread emergence of resistance. Imipenem/relebactam (IMI/REL) is a combination of the carbapenem imipenem with relebactam, a non-β-lactam β-lactamase inhibitor. It is active against most pathogenic GNB including many that are resistant to other agents. We compared its in vitro activity to six other agents against 490 GNB recovered exclusively from patients with cancer because such data are scarce. Clinical and Laboratory Standards Institute (CLSI) microbroth dilution methods were used for susceptibility testing. Whole genome sequencing (Illumina MiSeq) was performed on 30 selected isolates. IMI/REL was active against 98% of Enterobacterales and 87% of non-Enterobacterales isolates (excluding Stenotrophomonas maltophilia). It had potent activity against extended spectrum β-lactamase-producing Escherichia coli, Klebsiella pneumoniae, and other Enterobacterales (Enterobacter cloacae, Citrobacter Spp., and Serratia Spp.) and moderate activity against carbapenem-resistant Enterobacterales. IMI/REL had potent activity against Achromobacter Spp., non-multidrug resistant Pseudomonas aeruginosa, and Sphingomonas paucimobilis and moderate activity against multidrug resistant P. aeruginosa. Overall, IMI/REL was associated with the lowest number of nonsusceptible isolates compared with six other agents (imipenem, meropenem, cefepime, piperacillin/tazobactam, amikacin, and tigecycline) commonly used in patients with cancer. Whole genome sequencing performed on 30 resistant isolates (10 each of E. coli, K. pneumonia, and P. aeruginosa) did not reveal any predominant mechanism of resistance to IMI/REL. Its in vitro activity indicates that IMI/REL might have a role to play in the treatment of Gram-negative infections in patients with cancer.

Aminoglycosides in the Intensive Care Unit: What Is New in Population PK Modeling?

Background: Although aminoglycosides are often used as treatment for Gram-negative infections, optimal dosing regimens remain unclear, especially in ICU patients. This is due to a large between- and within-subject variability in the aminoglycoside pharmacokinetics in this population. Objective: This review provides comprehensive data on the pharmacokinetics of aminoglycosides in patients hospitalized in the ICU by summarizing all published PopPK models in ICU patients for amikacin, gentamicin, and tobramycin. The objective was to determine the presence of a consensus on the structural model used, significant covariates included, and therapeutic targets considered during dosing regimen simulations. Method: A literature search was conducted in the Medline/PubMed database, using the terms: ‘amikacin’, ‘gentamicin’, ‘tobramycin’, ‘pharmacokinetic(s)’, ‘nonlinear mixed effect’, ‘population’, ‘intensive care’, and ‘critically ill’. Results: Nineteen articles were retained where amikacin, gentamicin, and tobramycin pharmacokinetics were described in six, 11, and five models, respectively. A two-compartment model was used to describe amikacin and tobramycin pharmacokinetics, whereas a one-compartment model majorly described gentamicin pharmacokinetics. The most recurrent significant covariates were renal clearance and bodyweight. Across all aminoglycosides, mean interindividual variability in clearance and volume of distribution were 41.6% and 22.0%, respectively. A common consensus for an optimal dosing regimen for each aminoglycoside was not reached. Conclusions: This review showed models developed for amikacin, from 2015 until now, and for gentamicin and tobramycin from the past decades. Despite the growing challenges of external evaluation, the latter should be more considered during model development. Further research including new covariates, additional simulated dosing regimens, and external validation should be considered to better understand aminoglycoside pharmacokinetics in ICU patients.

Effect of Arabic Gum Aqueous Extract on Histological, Ultrastructural, Immunohistochemical and Biochemical Changes on Colistin-Induced Nephropathy in Male Albino Rats

Although colistin is an old antibiotic used in the treatment of Gram-negative infections, its usage is associated with nephrotoxicity. Arabic gum (AG) is an edible, dried gummy exudate used in the pharmaceutical and traditional treatment and has a protective effect against nephropathy through its antioxidant action. Aim of this study: This study was performed to demonstrate the role of the Arabic gum aqueous extract (AGAE) in repairing nephrotoxicity induced by colistin. Materials and methods: Forty adult male albino rats were divided equally into four groups. Group 1: Animals of this group served as control ones. Group II: Animals were treated with AGAE only 3 times a week for 8 weeks. Group III: Animals were subcutaneously injected with colistin accumulative dose 84 mg/kg (14mg/kg of body weight in 6 doses one every 2 hours). Group IV: Animals were treated with the accumulative dose of colistin and on the next day they received the AGAE three times a week for 8 weeks. At the end of each experiment, animals were sacrificed and the two kidneys were removed out and prepared for the histological and ultrastructural examination. Sera of animals were collected to determine urea, creatinine, malondialdyhide, and superoxide dismutase. Results: The treatment with AGAE efficiency improving colistin nephrotoxicity is evident from disappeared of most histopathological and ultrastructural alternations. Moreover, the immunohistochemical expression of PCNA and Bcl-2severly increased after colistin treatment. While the AGAE-treatment improved the expressions of PCNA and Bcl-2. Also, it is proven that the AGAE retrains the biochemical parameters determined to the normal ranges. Conclusion: AGAE exerts a protective effect against renal toxicity induced by colistin through its antioxidant, anti-inflammatory, and anti-apoptotic actions.

Pathogen-focused Clinical Development to Address Unmet Medical Need: Cefiderocol Targeting Carbapenem Resistance.

Historically, the regulatory requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for developing new antibiotics have not addressed pathogen-focused indications for drug approval. The design of the necessary randomized controlled trials traditionally involves the enrollment of patients with site-specific infections caused by susceptible as well as resistant pathogens. Cefiderocol has undergone a streamlined clinical development program to address serious carbapenem-resistant infections. The regulatory approach, and the pivotal clinical trials, differed between the FDA and EMA. In the United States, the APEKS-cUTI (Acinetobacter, Pseudomonas, Escherichia coli, Klebsiella, Stenotrophomonas–complicated urinary tract infection) study was conducted to provide the basis for FDA approval of a site-specific cUTI indication. The EMA, however, preferred the CREDIBLE-CR (A MultiCenter, RandomizED, Open-label ClInical Study of S-649266 or Best AvailabLE Therapy for the Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-negative Pathogens) study, in which patients with nosocomial pneumonia, bloodstream infections, or cUTIs were enrolled if they had a carbapenem-resistant pathogen. The resulting European label will be pathogen focused rather than infection site specific (ie, treatment of gram-negative infection in patients with limited treatment options). The implications and limitations of these different regulatory processes are discussed.

1485. Antimicrobial Activity of Ceftolozane-Tazobactam Tested Against Contemporary (2015–2017) Gram-Negative Isolates from Patients with Pneumonia in US Medical Centers

BackgroundCeftolozane-tazobactam (C-T) is a combination antipseudomonal cephalosporin and β-lactamase inhibitor. C-T has been approved in >50 countries for treating adults with complicated urinary tract infections, acute pyelonephritis, and complicated intra-abdominal infections in combination with metronidazole. The Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) monitors C-T resistance among Gram-negative (GN) isolates worldwide. In the current study, isolates were collected from US patients hospitalized with pneumonia (PIHP) from 2015–2017.MethodsA total of 4,337 GN isolates, including 2,102 Enterobacteriaceae (ENT) and 1,528 Pseudomonas aeruginosa (PSA) isolates, were collected in 2015–2017 from 30 US hospitals and tested for C-T susceptibility (S) by CLSI broth microdilution at JMI Laboratories. Only 1 isolate per patient per infection episode was included. Other antibiotics tested were amikacin (AMK), cefepime (FEP), ceftazidime (CAZ), colistin (COL), levofloxacin (LVX), meropenem (MEM), and piperacillin–tazobactam (TZP).-resistant (R) phenotypes analyzed were ENT R to doripenem, imipenem, or meropenem (CRE) and extended-spectrum β-lactamase (ESBL, non-CRE). Multidrug-resistant (MDR) isolates were identified as nonsusceptible (NS) to 3 or more antimicrobial classes. PSA phenotypes analyzed were CAZ-NS, MEM-NS, and TZP-NS.ResultsOf the 4,337 GN isolates, 3,820 (88.1%) had a C-T MIC ≤8 mg/L. The three most prevalent GN species isolated from PIHP were PSA (n = 1,528; 35.2%), Klebsiella pneumoniae (KPN, n = 562; 13.0%), and Escherichia coli (EC, n = 434; 10.0%). The %S of C-T and comparators for the top 3 pathogens are shown in the table. C-T showed activity against these isolates with %S of 96.5, 88.6, and 97.5% against EC, KPN, and PSA, respectively.ConclusionC-T demonstrated activity against the most prevalent contemporary GN isolates from PIHP in the US. C-T was the only β-lactam that had >88%S against all 3 species: EC, KPN, and PSA. C-T and COL were the only agents tested that had >95%S for EC and PSA pathogens in PIHP. For PSA, C-T maintained activity against isolates resistant to CAZ, TZP, and MEM. These data suggest that C-T may be a useful treatment for GN infections causing PIHP. Disclosures S. J. R. Arends, Merck: Research Contractor, Research support. D. Shortridge, Merck: Research Contractor, Research support. L. R. Duncan, Merck: Research Contractor, Research support. J. M. Streit, Merck: Research Contractor, Research support. R. K. Flamm, Merck: Research Contractor, Research support.

Rational Design and Synthesis of Modified Teixobactin Analogues: In Vitro Antibacterial Activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa.

Teixobactin, a recently discovered depsipeptide that binds to bacterial lipid II and lipid III, provides a promising molecular scaffold for the design of new antimicrobials. Herein, we describe the synthesis and antimicrobial evaluation of systematically modified teixobactin analogues. The replacement of the Ile11 residue with aliphatic isosteres, the modification of the guanidino group at residue 10 and the introduction of a rigidifying residue, that is, dehydroamino acid, into the macrocyclic ring generated useful structure-activity information. Extensive antimicrobial susceptibility assessment against a panel of clinically relevant Staphylococcus aureus and Propionibacterium acnes strains led to the identification of the new lead compound, [Arg(Me)10 ,Nle11 ]teixobactin, with an excellent bactericidal activity (minimum inhibitory concentration (MIC)=2-4 μg mL-1 ). Significantly, the antimicrobial activity of several of the teixobactin analogues against the pathogenic Gram-negative Pseudomonas aeruginosa was "restored" when combined with the sub-MIC concentration of the outer membrane-disruptive antibiotic colistin. The antimicrobial effectiveness of a [Tfn10 ,Nle11 ]teixobactin (32 μg mL-1 )-colistin (2 μg mL-1 ; 0.5×MIC) combination against P. aeruginosa PAO1 reveals, for the first time, an alternative therapeutic option in the treatment of Gram-negative infections.

Punica granatum improves renal function in gentamicin-induced nephropathy in rats via attenuation of oxidative stress

BackgroundGentamicin is widely used as an antibiotic for the treatment of gram negative infections. Evidences indicates that oxidative stress is involved in gentamicin-induced nephrotoxicity. In Ayurvedic medicine, Punica granatum Linn. is considered as 'a pharmacy unto itself”. It has been claimed in traditional literature, to treat various kidney ailments due to its antioxidant potential. ObjectiveTo explore the possible mechanism of action of methanolic extract of P.granatum leaves (MPGL) in exerting a protective effect on gentamicin-induced nephropathy. Material and methodsAnimals were administered with gentamicin (80 mg/kg/day i.m.) and simultaneously with MPGL (100, 200 and 400 mg/kg p.o.) or metformin (100 mg/kg p.o.) for 8 days. A satellite group was employed in order to check for reversibility of nephrotoxic effects post discontinuation of gentamicin administration. At the end of the study, all the rats were sacrificed and serum–urine parameters were investigated. Antioxidant enzymes and tumor necrosis factor alpha (TNF-α) levels were determined in the kidney tissues along with histopathological examination of kidneys. ResultsIncrease in serum creatinine, urea, TNF-α, lipid peroxidation along with fall in the antioxidant enzymes activity and degeneration of tubules, arterioles as revealed by histopathological examination confirmed the manifestation of nephrotoxicity caused due to gentamicin. Simultaneous administration of MPGL and gentamicin protected kidneys against nephrotoxic effects of gentamicin as evidenced from normalization of renal function parameters and amelioration of histopathological changes. ConclusionData suggests that MPGL attenuated oxidative stress associated renal injury by preserving antioxidant enzymes, reducing lipid peroxidation and inhibiting inflammatory mediators such as TNF-α.

Clinical outcomes and safety of colistin in treatment of gram negative infections: A prospective observational study

BackgroundDespite the fact that colistin has a significant activity against MDR gram-negative organisms, its toxicity limits its use. However, the limited therapeutic options due to increasing antibiotic resistance have made re-evaluation of older antibiotics inevitable. In contrast, lack of data to guide the usage of these drugs demands for studies on their safety and efficacy. This studies the clinical outcomes and safety of colistin at a tertiary care centre in Mumbai. Materials and methodsA prospective observational study was conducted at P.D. Hinduja Hospital, Mumbai for a period of seven months. Diagnosis of infection was based on CDC guidelines and APACHE II score was used to assess the severity of illness. Clinical and microbiological response to colistin was evaluated along with the incidence of nephrotoxicity (RIFLE criteria) and neurotoxicity. ResultsSixty-two patients (median age 56years, with documented gram negative bacterial infection and mean APACHE II score 22) received colistin. Clinically favourable response was seen in 71% patients. However, the mortality among the study population was 27%. Univariate analysis identified pneumonia and ICU admission as independent factors for adverse outcome. Deterioration of renal function was observed in 35.89% as per RIFLE criteria. 6 (9.6%) patients demonstrated neurotoxicity. ConclusionColistin is effective in treatment of gram negative infections and its use should be reappraised. However since colistin is the last resort it is imperative to make its best use to ensure that it remains as a safe and effective mode of treatment when need be.

Amikacin induced renal damage and the role of the antioxidants on neonatal rats

Amikacin (AK) is frequently used on the treatment of Gram-negative infections on neonates, but its usage is restricted because of nephrotoxicity. In this study, on neonatal rats, we aimed to investigate the effects of erythropoietin and vitamin E on AK induced nephrotoxicity. A total of 35 newborn Wistar Albino rats were divided into four groups: (1) injected with saline (serum physiological was administered to placebo controls), (2) injected with AK (1200 mg/kg), (3) injected with AK + vitamin E (150 mg/kg), (4) injected with AK + erythropoietin (EPO) (300 IU/kg/day). In renal tissue, AK levels were significantly high in all groups except the control. Tissue malondialdehyde (MDA) and nitric oxide (NO) levels were statistically higher in AK -treated group than the control. MDA and NO levels were significantly decreased with the administration of vitamin E and EPO. Glutathione peroxidase (GPX) levels were statistically low in AK group compared with the controls. The levels of GPX, in vitamin E group, were increased significantly. However, superoxide dismutase and catalase levels were not significantly different in none of the groups. Insulin-like growth factor-1 values in AK, EPO and vitamin E groups were significantly higher than the control group. Histomorphological changes such as tubular epithelial necrosis were seen in AK treated group. Histopathological improvements observed with EPO and vitamin E administration. AK nephrotoxicity is related to oxidative stress and is supported with biochemical and histopathological findings. Vitamin E and EPO, as antioxidants, can be useful renoprotective agents for ameliorating AK induced nephrotoxicity in neonates.

Evaluation of nephroprotective and nephrocurative activity of Solanum nigrum on gentamicin induced nephrotoxicity in experimental rats

Background: Aminoglycoside antibiotics are most commonly used drugs for the prevention and treatment of gram negative infections. Nephrotoxicity is the main side effect that restricts its long duration use. Modern medicines to treat nephrotoxicity are costly and also not vary effective. Solanum nigrum fruits, having potent antioxidant property can be used for nephroprotection as well as nephrocure. Methods: The study was carried out in two phases. Nephroprotective phase, 54 rats were randomized in 3 groups named G10, G20 & G30 according to 10, 20 & 30 days of treatment. Each group was randomized in three subgroups i.e. control C group [received normal saline (2 ml/100 gm/day) daily for test duration], GT group [received normal saline (2 ml/100 gm/day) daily for test duration & intra-peritoneal gentamicin (40mg/kg) for last five days] & SNT group [received orally S.nigrum (200 mg/kg/day) daily for the test duration and intra-peritoneal gentamicin (40 mg/kg) for last five days]. Rats were sacrificed 24 hours after the last dose of gentamicin (on 11 th , 21 st and 31 st day). In nephrocurative phase, 72 rats were randomised in two groups of 36 rats each. Group-1 received intra-peritoneal gentamicin (40 mg/dl) for five days. Group-2 received intra-peritoneal gentamicin (40 mg/dl) for five days and then S.nigrum (200 mg/kg/day) orally till the rats are sacrificed. Six rats from each group were sacrificed on 3 rd , 5 th , 7 th , 10 th , 12 th and 14 th day after administration of last dose of gentamicin. Blood sample were taken for evaluation of BUN and serum creatinine. Results: There was significant decrease in BUN and serum creatinine values as compared to GT group in all test duration in phase-1. In phase two there was no significant difference of these markers in two groups. Conclusions: S.nigrum fruits extract provide nephroprotection against gentamicin induced nephrotoxicity.

Elizabethkingia Meningoseptica: An Emerging Pathogen in Pediatric Patients.

E. meningoseptica is widely distributed in fresh and salt waters, in the soil, and in some animals but is not considered a normal human microflora. It is a gram negative non-fermentative bacillus which is found in the hospital environment and associated with nosocomial infections. It causes various disease like endocarditis, peritonitis, bacteremia, pneumonia, pediatric meningitis. It is mostly associated with infections in the immunocompromised patients. Recognition of E. meningoseptica is of paramount importance for clinicians since multi-drug resistance is common for this organism and secondly it is resistant to antibiotics which are normally used in the treatment of gram negative infections and is sensitive to vancomyin. So knowledge about this organism and its sensitivity will help clinicans to start the antibiotic of choice promptly. We here reported 2 cases of Elizabethkingia meningoseptica in blood and pleural fluid from immunocompromised pediatric patients. JMS 2014;17(2):61-63

Preserving the efficacy of front-line fluoroquinolones through selective use to optimise clinical outcomes

As antibiotic resistance is increasing worldwide, it is important to prescribe fluoroquinolone (FQ) antibiotics appropriately for a given infection to preserve class efficacy. Clinical studies reveal good efficacy and tolerability of the currently approved FQs (ciprofloxacin, levofloxacin and moxifloxacin) in a wide range of community- and hospital-acquired infections. However, certain features supporting their clinical efficacy suggest a rationale for inclusion of moxifloxacin and ciprofloxacin with complementary clinical benefit on a formulary rather than levofloxacin alone; it may also be more cost-effective. Ciprofloxacin has advantages over levofloxacin in the treatment of Gram-negative infections, whilst moxifloxacin has certain efficacy and ease of use advantages over levofloxacin in respiratory tract infections. To preserve the potential of FQs and to minimise the risk of resistance selection, agents with the highest in vitro activity and supportive pharmacokinetic/pharmacodynamic profiles should be used first-line, as appropriate for local guidelines and prescribing information.

How Does Colistin-Induced Nephropathy Develop and Can It Be Treated?

Colistin is an old antibiotic used in the treatment of Gram-negative infections. It was once suspended because of its nephrotoxic effect but has since been reintroduced due to multidrug-resistant bacterial infections. The pathogenesis of colistin-associated nephropathy has not been clarified, and there is currently no effective therapeutic or prophylactic agent available. The aim of this study was to investigate the roles of caspase-associated apoptosis and caspase 1, calpain 1, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) expression in the pathogenesis of colistin-associated nephrotoxicity and the effect of grape seed proanthocyanidin extract (GSPE) in preventing it. Twenty-four rats were divided into three groups: control, colistin, and colistin plus GSPE (colistin+GSPE). Colistin-associated nephropathy was induced by the administration of 300,000 IU/kg of body weight/day colistin intraperitoneally for 7 days. The experiment was discontinued on the seventh day. Blood was collected for measurements of blood urea nitrogen (BUN) and creatinine levels. Histopathological examination of kidney tissue and caspase 1 and 3, iNOS, eNOS, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and calpain 1 staining was also performed. Significant increases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed for the colistin group compared to the control group. Significant decreases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed in the colistin+GSPE group compared to the colistin group. Our study shows, for the first time in the literature, that caspase-mediated apoptosis, iNOS, caspase 1, and calpain 1 are involved in the pathogenesis of colistin-associated nephropathy. GSPE had a renoprotective effect, as shown by the lowered levels of these mediators.

Dose-related protecting effects of vitamin C in gentamicin-induced rat nephrotoxicity: a histopathologic and biochemical study

Gentamicin remains the mainstay in treatment of gram-negative infections, despite its potential ototoxicity and nephrotoxicity. In this study, we investigated dose-related protecting effects of vitamin C against gentamicin-induced rat nephrotoxicity. Hence, 50 male albino Wistar rats were randomly divided into five equal groups to receive a corresponding dose of either normal saline as control, vitamin C (200 mg/kg/bw, i.m.) or gentamicin alone (80 mg/kg/bw, i.m.) or in combination with vitamin C at low dose (200 mg/kg/bw, i.m.; LVG) and high dose (600 mg/kg/bw, i.m.) for 9 days. Daily administration of gentamicin at a dose of 80 mg/kg resulted in a significant increase in oxidative stress in renal tissues and plasma and a concomitant decrease in the creatinine clearance and renal blood flow as result of early hemodynamic toxicity. Histopathological examinations revealed acute tubular necrosis with hyaline cast formation triggered by gentamicin over 9 days of experiment, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies showed protecting effects of supplemented vitamin C at a high dose, including slowdown in the urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and the ATPase activity up to 50% when compared to controls and low-dose rats (LVG). In high-dose animals, normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that antioxidant properties of vitamin C consistently increase with dose intensity. The present study also provided evidence that high dose of vitamin C prevented both functional and histological renal changes induced by gentamicin in rats, more efficient than low dose of the vitamin.